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Liu L, Oh C, Lim MA, Zheng S, Piao Y, Ohm S, Shan Y, Piao S, Shen S, Kim YI, Won HR, Chang JW, Kim MG, Kim DH, Kim JW, Jung SN, Koo BS. Dual blockage of P-cadherin and c-Met synergistically inhibits the growth of head and neck cancer. Cell Oncol (Dordr) 2025:10.1007/s13402-025-01061-w. [PMID: 40392501 DOI: 10.1007/s13402-025-01061-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 03/26/2025] [Indexed: 05/22/2025] Open
Abstract
PURPOSE P-cadherin (CDH3) is a transmembrane protein that plays a crucial role in maintaining the structural integrity of epithelial tissue and homeostasis. Its role in carcinogenesis remains a subject of debate, as its behavior can vary depending on the molecular context and the specific tumor cell model under study. In this study, we explored the role of P-cadherin in head and neck squamous cell carcinoma (HNSCC) and the mechanisms underlying its function. METHODS We analyzed P-cadherin expression in HNSCC patients using The Cancer Genome Atlas (TCGA), The Chungnam National University Hospital (CNUH) cohort and Gene Expression Omnibus (GEO) database. For in vitro functional analysis, we conducted proliferation, migration, invasion, and western blot assays after either suppressing or overexpressing P-cadherin. For in vivo functional analysis, we utilized mouse xenograft models. RESULTS P-cadherin was significantly overexpressed in tumor samples compared to normal samples in the TCGA-HNSCC and CNUH-HNSCC cohorts. P-cadherin knockdown resulted in decreased proliferation, migration, and invasion compared to control cells, while P-cadherin overexpression increased cell proliferation and migration in HNSCC cells. We discovered that c-Met functions as an upstream regulator of P-cadherin. Surprisingly, we found that P-cadherin knockdown increased the phosphorylation of c-Met and STAT3. Combining P-cadherin siRNA with the c-Met inhibitor SU11274 or c-Met siRNA resulted in a more effective reduction in HNSCC cell growth, both in vitro and in vivo, compared to either treatment alone. CONCLUSION Our study uncovered a previously unknown aspect of P-cadherin-mediated c-Met regulation. The enhanced activation of c-Met/STAT3 following P-cadherin inhibition could be responsible for the survival of resistant tumor cells. Therefore, dual inhibition of P-cadherin and c-Met may be an effective approach for treating HNSCC.
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Affiliation(s)
- Lihua Liu
- Department of Nutrition, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China
| | - Chan Oh
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Mi Ae Lim
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Sicong Zheng
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Yudan Piao
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Sun Ohm
- Department of Biology, Temple University, Philadelphia, PA, 19122, USA
| | - Yujuan Shan
- Department of Nutrition, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China
| | - Shuyu Piao
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Shan Shen
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Young Il Kim
- Department of Radiation Oncology, Chungnam National University Sejong Hospital, Sejong, 30099, Republic of Korea
| | - Ho-Ryun Won
- Department of Otorhinolaryngology-Head and Neck Surgery, Chungnam National University Sejong Hospital, Sejong, Republic of Korea
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Jae Won Chang
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Min-Gyu Kim
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Doh Hoon Kim
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea
| | - Ji Won Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Chungnam National University Sejong Hospital, Sejong, Republic of Korea
| | - Seung-Nam Jung
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.
| | - Bon Seok Koo
- Department of Nutrition, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China.
- Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, 266, Munhwa-ro, Jung-gu, Daejeon, 35015, Republic of Korea.
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
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He C, Yu J, Mao S, Yang S, Jiang X, Huang L, Li M, He Y, Zhang X, Xiang X. SHP2 inhibition and adjuvant therapy synergistically target KIT-mutant GISTs via ERK1/2-regulated GSK3β/cyclin D1 pathway. Clin Transl Med 2025; 15:e70231. [PMID: 39981588 PMCID: PMC11843164 DOI: 10.1002/ctm2.70231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 01/22/2025] [Accepted: 02/03/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Most gastrointestinal stromal tumours (GISTs) are driven by KIT proto-oncogene, receptor tyrosine kinase (KIT). Targeted treatment with imatinib has been successful in primary GIST patients. However, resistance and relapse gradually develop due to secondary KIT mutations. Identifying novel therapeutic targets for advanced GIST with KIT mutants is critical. METHODS Clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 gene editing, immunoblotting, immunoprecipitation and cell-based assays were used to characterise the role of Src homology region 2 domain-containing phosphatase 2 (SHP2) in GIST. Immunoblotting, cell cycle analysis, transcriptome analysis and rescue experiments were performed to investigate the molecular mechanisms underlying SHP2 inhibition. Synergistic effects of SHP2 inhibition with approved KIT tyrosine kinase inhibitors (TKIs) were demonstrated using cell proliferation assay, spheroid formation assay, cell cycle analysis and immunoblotting. The combination of SHP2 inhibition and imatinib was further evaluated in GIST mouse models. RESULTS In KIT-mutant GIST, SHP2 was hyperactive and coprecipitated with KIT. Activated SHP2 transduced signals from KIT to the downstream MAPK/ERK pathway. SHP2 inhibition significantly reduced cell viability and arrested cell at G0/G1 phase in GIST cells. Mechanistically, SHP2 regulated the MAPK/ERK, GSK3β/cyclin D1 and mTORC1 pathways in GIST. Specifically, SHP2 inhibition relieved GSK3β self-inhibition, leading to a reduction in cyclin D1 via phosphorylation at Thr286 and subsequent G0/G1 cell cycle arrest. Rescue experiments confirmed that cyclin D1 is functional and critical for cell proliferation. Additionally, SHP2 inhibition synergised with approved KIT TKIs in inhibiting GIST cells. In GIST mouse models, SHP2 inhibitor (SHP099) combined with imatinib significantly inhibited proliferation of imatinib-sensitive and -insensitive GIST cells. CONCLUSIONS SHP2 functioned as a key signal transducer for the MAPK/ERK signalling pathway and regulated the cell cycle through GSK3β/cyclin D1/Rb pathway. SHP2 inhibition demonstrates significant efficacy towards GIST cells and synergises with approved TKIs. Therefore, SHP2 represents a promising therapeutic target for advanced GIST. KEY POINTS SHP2 plays a pivotal role as a signal transducer in the MAPK/ERK signaling pathway. SHP2 controls the cell cycle via the GSK3β/cyclin D1/Rb pathway in oncogenic KIT-driven GIST. Inhibition of SHP2 synergizes with adjuvant therapy drugs in inhibiting KIT-driven GIST with primary and secondary mutations both in vitro and in vivo.
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Affiliation(s)
- Chunxiao He
- Scientific Research CenterThe Seventh Affiliated Hospital, Sun Yat‐sen UniversityShenzhenGuangdongChina
| | - Jiaying Yu
- Scientific Research CenterThe Seventh Affiliated Hospital, Sun Yat‐sen UniversityShenzhenGuangdongChina
| | - Shuang Mao
- Scientific Research CenterThe Seventh Affiliated Hospital, Sun Yat‐sen UniversityShenzhenGuangdongChina
| | - Shaohua Yang
- Guangdong Provincial Key Laboratory of Digestive Cancer ResearchThe Seventh Affiliated Hospital, Sun Yat‐sen UniversityShenzhenGuangdongChina
| | - Xianming Jiang
- Guangdong Provincial Key Laboratory of Digestive Cancer ResearchThe Seventh Affiliated Hospital, Sun Yat‐sen UniversityShenzhenGuangdongChina
| | - Lei Huang
- School of MedicineSun Yat‐sen UniversityShenzhenGuangdongChina
| | - Mingzhe Li
- Guangdong Provincial Key Laboratory of Digestive Cancer ResearchThe Seventh Affiliated Hospital, Sun Yat‐sen UniversityShenzhenGuangdongChina
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer ResearchThe Seventh Affiliated Hospital, Sun Yat‐sen UniversityShenzhenGuangdongChina
| | - Xinhua Zhang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdongChina
| | - Xi Xiang
- Scientific Research CenterThe Seventh Affiliated Hospital, Sun Yat‐sen UniversityShenzhenGuangdongChina
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He C, Wang Z, Yu J, Mao S, Xiang X. Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update. Curr Treat Options Oncol 2024; 25:1390-1405. [PMID: 39441520 PMCID: PMC11541409 DOI: 10.1007/s11864-024-01272-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2024] [Indexed: 10/25/2024]
Abstract
OPINION STATEMENT Gastrointestinal stromal tumor (GIST) is characterized by well-defined oncogenes. Despite the significant improvement in treatment outcomes with adjuvant imatinib therapy for patients, drug resistance remains a major challenge for GIST therapy. This review focuses on the mechanisms contributing to drug resistance phenotype in GIST, such as primary imatinib-resistant mutants, secondary mutations, non-covalent binding of TKI to its target, tumor heterogeneity, re-activation of pro-survival/proliferation pathways through non-KIT/PDGFRA kinases, and loss of therapeutic targets in wild-type GIST. Corresponding suggestions are proposed to overcome drug-resistance phenotype of GIST. This review also summarizes the suitability of currently approved TKIs on different KIT/PDGFRA mutations and updates related clinical trials. Recent potent drugs and emerging strategies against advanced GISTs in clinical trials are presented. Additionally, metabolic intervention offers a new avenue for clinical management in GIST. A landscape of metabolism in GIST and metabolic changes under imatinib treatment are summarized based on currently published data. The OXPHOS pathway is a promising therapeutic target in combination with TKI against sensitive KIT/PDGFRA mutants. Comprehensive understanding of the above resistance mechanisms, experimental drugs/strategies and metabolic changes is critical to implement the proper therapy strategy and improve the clinical therapy outcomes for GIST.
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Affiliation(s)
- Chunxiao He
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
| | - Zilong Wang
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jiaying Yu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Shuang Mao
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xi Xiang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
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Suarez CF, Harb OA, Robledo A, Largoza G, Ahn JJ, Alley EK, Wu T, Veeraragavan S, McClugage ST, Iacobas I, Fish JE, Kan PT, Marrelli SP, Wythe JD. MEK signaling represents a viable therapeutic vulnerability of KRAS-driven somatic brain arteriovenous malformations. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.15.594335. [PMID: 38766159 PMCID: PMC11101126 DOI: 10.1101/2024.05.15.594335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Brain arteriovenous malformations (bAVMs) are direct connections between arteries and veins that remodel into a complex nidus susceptible to rupture and hemorrhage. Most sporadic bAVMs feature somatic activating mutations within KRAS, and endothelial-specific expression of the constitutively active variant KRASG12D models sporadic bAVM in mice. By leveraging 3D-based micro-CT imaging, we demonstrate that KRASG12D-driven bAVMs arise in stereotypical anatomical locations within the murine brain, which coincide with high endogenous Kras expression. We extend these analyses to show that a distinct variant, KRASG12C, also generates bAVMs in predictable locations. Analysis of 15,000 human patients revealed that, similar to murine models, bAVMs preferentially occur in distinct regions of the adult brain. Furthermore, bAVM location correlates with hemorrhagic frequency. Quantification of 3D imaging revealed that G12D and G12C alter vessel density, tortuosity, and diameter within the mouse brain. Notably, aged G12D mice feature increased lethality, as well as impaired cognition and motor function. Critically, we show that pharmacological blockade of the downstream kinase, MEK, after lesion formation ameliorates KRASG12D-driven changes in the murine cerebrovasculature and may also impede bAVM progression in human pediatric patients. Collectively, these data show that distinct KRAS variants drive bAVMs in similar patterns and suggest MEK inhibition represents a non-surgical alternative therapy for sporadic bAVM.
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Niessner H, Hüsch A, Kosnopfel C, Meinhardt M, Westphal D, Meier F, Schilling B, Sinnberg T. Exploring the In Vitro and In Vivo Therapeutic Potential of BRAF and MEK Inhibitor Combination in NRAS-Mutated Melanoma. Cancers (Basel) 2023; 15:5521. [PMID: 38067230 PMCID: PMC10705743 DOI: 10.3390/cancers15235521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 10/16/2024] Open
Abstract
INTRODUCTION Patients with NRAS-mutant metastatic melanoma often have an aggressive disease requiring a fast-acting, effective therapy. The MEK inhibitor binimetinib shows an overall response rate of 15% in patients with NRAS-mutant melanoma, providing a backbone for combination strategies. Our previous studies demonstrated that in NRAS-mutant melanoma, the antitumor activity of the MEK inhibitor binimetinib was significantly potentiated by the BRAFV600E/K inhibitor encorafenib through the induction of ER stress, leading to melanoma cell death by apoptotic mechanisms. Encorafenib combined with binimetinib was well tolerated in a phase III trial showing potent antitumor activity in BRAF-mutant melanoma, making a rapid evaluation in NRAS-mutant melanoma imminently feasible. These data provide a mechanistic rationale for the evaluation of binimetinib combined with encorafenib in preclinical and clinical studies on NRAS-mutant metastatic melanoma. METHODS The combination of BRAFi plus MEKi was tested in a monolayer culture of patient-derived cell lines and in corresponding patient-derived tissue slice cultures of NRAS-mutant melanoma. To investigate the treatment in vivo, NSG (NOD. Cg-PrkdcscidIl2rgtm1Wjl/SzJ) mice were subcutaneously injected with three different BRAF wild-type melanoma models harboring oncogenic NRAS mutations and treated orally with encorafenib (6 mg/kg body weight, daily) with or without binimetinib (8 mg/kg body weight, twice daily). In parallel, an individual healing attempt was carried out by treating one patient with an NRAS-mutated tumor. RESULTS Encorafenib was able to enhance the inhibitory effect on cell growth of binimetinib only in the cell line SKMel147 in vitro. It failed to enhance the apoptotic effect found in two other NRAS-mutated cell lines. Encorafenib led to a hyperactivation of ERK which could be reduced with the combinational treatment. In two of the three patient-derived tissue slice culture models of NRAS-mutant melanomas, a slight tendency of a combinatorial effect was seen which was not significant. Encorafenib showed a slight induction of the ER stress genes ATF4, CHOP, and NUPR1. The combinational treatment was able to enhance this effect, but not significantly. In the mouse model, the combination therapy of encorafenib with binimetinib resulted in reduced tumor growth compared to the control and encorafenib groups; however, the best effect in terms of tumor growth inhibition was measured in the binimetinib therapy group. The therapy showed no effect in an individual healing attempt for a patient suffering from metastatic, therapy-refractory NRAS-mutated melanoma. CONCLUSION In in vitro and ex vivo settings, the combination therapy was observed to elicit a response; however, it did not amplify the efficacy observed with binimetinib alone, whereas in a patient, the combinational treatment remained ineffective. The preclinical in vivo data showed no increased combinatorial effect. However, the in vivo effect of binimetinib as monotherapy was unexpectedly high in the tested regimen. Nevertheless, binimetinib proved to be advantageous in the treatment of melanoma in vivo and led to high rates of apoptosis in vitro; hence, it still seems to be a good base for combination with other substances in the treatment of patients with NRAS-mutant melanoma.
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Affiliation(s)
- Heike Niessner
- Division of Dermatooncology, Department of Dermatology, University of Tuebingen, Liebermeisterstr. 25, 72076 Tuebingen, Germany;
- Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”, 72076 Tuebingen, Germany
| | - Anna Hüsch
- Division of Dermatooncology, Department of Dermatology, University of Tuebingen, Liebermeisterstr. 25, 72076 Tuebingen, Germany;
| | - Corinna Kosnopfel
- Department of Hematology, Oncology and Pneumology, University Hospital Muenster, 48149 Muenster, Germany;
| | - Matthias Meinhardt
- Department of Pathology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany;
- National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany; (D.W.); (F.M.)
| | - Dana Westphal
- National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany; (D.W.); (F.M.)
- Department of Dermatology, Carl Gustav Carus Medical Center, TU Dresden, 01307 Dresden, Germany
| | - Friedegund Meier
- National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany; (D.W.); (F.M.)
- Department of Dermatology, Carl Gustav Carus Medical Center, TU Dresden, 01307 Dresden, Germany
- Center for Regenerative Therapies Dresden, TU Dresden, 01307 Dresden, Germany
| | - Bastian Schilling
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany;
| | - Tobias Sinnberg
- Division of Dermatooncology, Department of Dermatology, University of Tuebingen, Liebermeisterstr. 25, 72076 Tuebingen, Germany;
- Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”, 72076 Tuebingen, Germany
- Department of Dermatology, Venereology and Allergology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
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Macaya I, Roman M, Welch C, Entrialgo-Cadierno R, Salmon M, Santos A, Feliu I, Kovalski J, Lopez I, Rodriguez-Remirez M, Palomino-Echeverria S, Lonfgren SM, Ferrero M, Calabuig S, Ludwig IA, Lara-Astiaso D, Jantus-Lewintre E, Guruceaga E, Narayanan S, Ponz-Sarvise M, Pineda-Lucena A, Lecanda F, Ruggero D, Khatri P, Santamaria E, Fernandez-Irigoyen J, Ferrer I, Paz-Ares L, Drosten M, Barbacid M, Gil-Bazo I, Vicent S. Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer. Nat Commun 2023; 14:6332. [PMID: 37816716 PMCID: PMC10564741 DOI: 10.1038/s41467-023-41828-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 09/20/2023] [Indexed: 10/12/2023] Open
Abstract
Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.
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Affiliation(s)
- Irati Macaya
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
| | - Marta Roman
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
- Division of Hematology and Oncology, University of California San Francisco, San Francisco, CA, USA
| | - Connor Welch
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
| | | | - Marina Salmon
- Experimental Oncology Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Alba Santos
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Iker Feliu
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
| | - Joanna Kovalski
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- Department of Urology, University of California San Francisco, San Francisco, CA, USA
| | - Ines Lopez
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
| | - Maria Rodriguez-Remirez
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
| | - Sara Palomino-Echeverria
- Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra, Pamplona, Spain
| | - Shane M Lonfgren
- Stanford Institute for Immunity, Transplantation and Infection, Stanford, CA, USA
- Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Macarena Ferrero
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Molecular Oncology Laboratory, Fundación Para La Investigación del Hospital General Universitario de Valencia, Valencia, Spain
- Mixed Unit TRIAL (Principe Felipe Research Centre & Fundación para la Investigación del Hospital General Universitario de Valencia), Valencia, Spain
| | - Silvia Calabuig
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Molecular Oncology Laboratory, Fundación Para La Investigación del Hospital General Universitario de Valencia, Valencia, Spain
- Mixed Unit TRIAL (Principe Felipe Research Centre & Fundación para la Investigación del Hospital General Universitario de Valencia), Valencia, Spain
- Department of Pathology, Universitat de Valencia, Valencia, Spain
| | - Iziar A Ludwig
- University of Navarra, Center for Applied Medical Research, Molecular Therapies Program, Pamplona, Spain
| | - David Lara-Astiaso
- University of Navarra, Center for Applied Medical Research, Genomics Platform, Pamplona, Spain
| | - Eloisa Jantus-Lewintre
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Molecular Oncology Laboratory, Fundación Para La Investigación del Hospital General Universitario de Valencia, Valencia, Spain
- Mixed Unit TRIAL (Principe Felipe Research Centre & Fundación para la Investigación del Hospital General Universitario de Valencia), Valencia, Spain
- Department of Pathology, Universitat de Valencia, Valencia, Spain
| | - Elizabeth Guruceaga
- University of Navarra, Center for Applied Medical Research, Bioinformatics Platform, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- ProteoRed-Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Shruthi Narayanan
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
- Clinica Universidad de Navarra, Department of Medical Oncology, Pamplona, Spain
| | - Mariano Ponz-Sarvise
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Clinica Universidad de Navarra, Department of Medical Oncology, Pamplona, Spain
| | - Antonio Pineda-Lucena
- University of Navarra, Center for Applied Medical Research, Molecular Therapies Program, Pamplona, Spain
| | - Fernando Lecanda
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- University of Navarra, Department of Pathology, Anatomy and Physiology, Pamplona, Spain
| | - Davide Ruggero
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- Department of Urology, University of California San Francisco, San Francisco, CA, USA
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
| | - Purvesh Khatri
- Department of Urology, University of California San Francisco, San Francisco, CA, USA
- Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra, Pamplona, Spain
| | - Enrique Santamaria
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- ProteoRed-Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Joaquin Fernandez-Irigoyen
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- ProteoRed-Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Irene Ferrer
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Luis Paz-Ares
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
- Medical School, Universidad Complutense, Madrid, Spain
| | - Matthias Drosten
- Experimental Oncology Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO), Madrid, Spain
- Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, Salamanca, Spain
| | - Mariano Barbacid
- Experimental Oncology Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO), Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ignacio Gil-Bazo
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- Clinica Universidad de Navarra, Department of Medical Oncology, Pamplona, Spain
- Department of Oncology, Fundación Instituto Valenciano de Oncología, Valencia, Spain
| | - Silve Vicent
- University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
- University of Navarra, Department of Pathology, Anatomy and Physiology, Pamplona, Spain.
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7
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More P, Ngaffo JAM, Goedtel-Armbrust U, Hähnel PS, Hartwig UF, Kindler T, Wojnowski L. Transcriptional Response to Standard AML Drugs Identifies Synergistic Combinations. Int J Mol Sci 2023; 24:12926. [PMID: 37629110 PMCID: PMC10455220 DOI: 10.3390/ijms241612926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Unlike genomic alterations, gene expression profiles have not been widely used to refine cancer therapies. We analyzed transcriptional changes in acute myeloid leukemia (AML) cell lines in response to standard first-line AML drugs cytarabine and daunorubicin by means of RNA sequencing. Those changes were highly cell- and treatment-specific. By comparing the changes unique to treatment-sensitive and treatment-resistant AML cells, we enriched for treatment-relevant genes. Those genes were associated with drug response-specific pathways, including calcium ion-dependent exocytosis and chromatin remodeling. Pharmacological mimicking of those changes using EGFR and MEK inhibitors enhanced the response to daunorubicin with minimum standalone cytotoxicity. The synergistic response was observed even in the cell lines beyond those used for the discovery, including a primary AML sample. Additionally, publicly available cytotoxicity data confirmed the synergistic effect of EGFR inhibitors in combination with daunorubicin in all 60 investigated cancer cell lines. In conclusion, we demonstrate the utility of treatment-evoked gene expression changes to formulate rational drug combinations. This approach could improve the standard AML therapy, especially in older patients.
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Affiliation(s)
- Piyush More
- Department of Pharmacology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, Germany; (J.A.M.N.); (U.G.-A.); (L.W.)
| | - Joëlle Aurelie Mekontso Ngaffo
- Department of Pharmacology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, Germany; (J.A.M.N.); (U.G.-A.); (L.W.)
- Leibniz Institute for New Materials, 66123 Saarbrücken, Germany
| | - Ute Goedtel-Armbrust
- Department of Pharmacology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, Germany; (J.A.M.N.); (U.G.-A.); (L.W.)
| | - Patricia S. Hähnel
- University Cancer Center (UCT) Mainz, Johannes Gutenberg-University, 55131 Mainz, Germany; (P.S.H.); (T.K.)
- Department of Hematology & Medical Oncology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, Germany;
| | - Udo F. Hartwig
- Department of Hematology & Medical Oncology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, Germany;
- Research Center of Immunotherapy, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, Germany
| | - Thomas Kindler
- University Cancer Center (UCT) Mainz, Johannes Gutenberg-University, 55131 Mainz, Germany; (P.S.H.); (T.K.)
- Department of Hematology & Medical Oncology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, Germany;
| | - Leszek Wojnowski
- Department of Pharmacology, University Medical Center, Johannes Gutenberg-University, 55131 Mainz, Germany; (J.A.M.N.); (U.G.-A.); (L.W.)
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8
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Aguilar-Valdés A, González-Vela F, Sánchez-Vidal H, Martínez-Aguilar J. A proteomic signature and potential pharmacological opportunities in the adaptive resistance to MEK and PI3K kinase inhibition in pancreatic cancer cells. Proteomics 2023; 23:e2300041. [PMID: 37140101 DOI: 10.1002/pmic.202300041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/23/2023] [Accepted: 04/18/2023] [Indexed: 05/05/2023]
Abstract
Pancreatic cancer is one of the most lethal cancer types and is becoming a leading cause of cancer-related deaths. The limited benefit offered by chemotherapy agents has propelled the search for alternative approaches that target specific molecular drivers of cancer growth and progression. Mutant KRas and effector pathways Raf/MEK/ERK and PI3K/Akt are key players in pancreatic cancer; however, preclinical studies have shown adaptive tumour response to combined MEK and PI3K kinase inhibition leading to treatment resistance. There is a critical unmet need to decipher the molecular basis underlying adaptation to this targeted approach. Here, we aimed to identify common protein expression alterations associated with adaptive resistance in KRas-mutant pancreatic cancer cells, and test if it can be overcome by selected already available small molecule drugs. We found a group of 14 proteins with common expression change in resistant cells, including KRas, caveolin-1, filamin-a, eplin, IGF2R and cytokeratins CK-8, -18 and -19. Notably, several proteins have previously been observed in pancreatic cancer cells with intrinsic resistance to the combined kinase inhibition treatment, suggesting a proteomic signature. We also found that resistant cells are sensitive to small molecule drugs ERK inhibitor GDC-0994, S6K1 inhibitor DG2 and statins.
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Affiliation(s)
- Alain Aguilar-Valdés
- Red de Apoyo a la Investigación, Coordinación de la Investigación Científica, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Francisco González-Vela
- Red de Apoyo a la Investigación, Coordinación de la Investigación Científica, Universidad Nacional Autónoma de México, Mexico City, Mexico
- Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Hilda Sánchez-Vidal
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Juan Martínez-Aguilar
- Red de Apoyo a la Investigación, Coordinación de la Investigación Científica, Universidad Nacional Autónoma de México, Mexico City, Mexico
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9
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Sigaud R, Rösch L, Gatzweiler C, Benzel J, von Soosten L, Peterziel H, Selt F, Najafi S, Ayhan S, Gerloff XF, Hofmann N, Büdenbender I, Schmitt L, Foerster KI, Burhenne J, Haefeli WE, Korshunov A, Sahm F, van Tilburg CM, Jones DTW, Pfister SM, Knoerzer D, Kreider BL, Sauter M, Pajtler KW, Zuckermann M, Oehme I, Witt O, Milde T. The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models. Neuro Oncol 2023; 25:566-579. [PMID: 35882450 PMCID: PMC10013652 DOI: 10.1093/neuonc/noac183] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. METHODS We investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAFV600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing. RESULTS Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of antiproliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival. CONCLUSIONS These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.
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Affiliation(s)
- Romain Sigaud
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Lisa Rösch
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Charlotte Gatzweiler
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,Faculty of Medicine, Heidelberg University, Heidelberg, Germany
| | - Julia Benzel
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.,Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Laura von Soosten
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.,Preclinical Modeling Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Heike Peterziel
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Florian Selt
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
| | - Sara Najafi
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
| | - Simay Ayhan
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Xenia F Gerloff
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
| | - Nina Hofmann
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Preclinical Modeling Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Isabel Büdenbender
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Lukas Schmitt
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Pediatric Soft Tissue Sarcoma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kathrin I Foerster
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Jürgen Burhenne
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Walter E Haefeli
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Andrey Korshunov
- Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.,Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Felix Sahm
- Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.,Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Cornelis M van Tilburg
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
| | - David T W Jones
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stefan M Pfister
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,KiTZ Clinical Trial Unit, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.,Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | | | - Max Sauter
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Kristian W Pajtler
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.,KiTZ Clinical Trial Unit, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
| | - Marc Zuckermann
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Preclinical Modeling Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ina Oehme
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Olaf Witt
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
| | - Till Milde
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit, Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
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10
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Khan S, Budamagunta V, Zhou D. Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies. Adv Cancer Res 2023; 159:145-184. [PMID: 37268395 DOI: 10.1016/bs.acr.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
KRAS, a predominant member of the RAS family, is the most frequently mutated oncogene in human pancreatic cancer (∼95% of cases). Mutations in KRAS lead to its constitutive activation and activation of its downstream signaling pathways such as RAF/MEK/ERK and PI3K/AKT/mTOR that promote cell proliferation and provide apoptosis evasion capabilities to cancer cells. KRAS had been considered 'undruggable' until the discovery of the first covalent inhibitor targeting the G12C mutation. While G12C mutations are frequently found in non-small cell lung cancer, these are relatively rare in pancreatic cancer. On the other hand, pancreatic cancer harbors other KRAS mutations such as G12D and G12V. The inhibitors targeting G12D mutation (such as MRTX1133) have been recently developed, whereas those targeting other mutations are still lacking. Unfortunately, KRAS inhibitor monotherapy-associated resistance hinders their therapeutic efficacy. Therefore, various combination strategies have been tested and some yielded promising results, such as combinations with receptor tyrosine kinase, SHP2, or SOS1 inhibitors. In addition, we recently demonstrated that the combination of sotorasib with DT2216 (a BCL-XL-selective degrader) synergistically inhibits G12C-mutated pancreatic cancer cell growth in vitro and in vivo. This is in part because KRAS-targeted therapies induce cell cycle arrest and cellular senescence, which contributes to therapeutic resistance, while their combination with DT2216 can more effectively induce apoptosis. Similar combination strategies may also work for G12D inhibitors in pancreatic cancer. This chapter will review KRAS biochemistry, signaling pathways, different mutations, emerging KRAS-targeted therapies, and combination strategies. Finally, we discuss challenges associated with KRAS targeting and future directions, emphasizing pancreatic cancer.
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Affiliation(s)
- Sajid Khan
- Department of Biochemistry & Structural Biology, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
| | - Vivekananda Budamagunta
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, United States; Genetics and Genomics Graduate Program, Genetics Institute, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Daohong Zhou
- Department of Biochemistry & Structural Biology, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States; Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.
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11
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Yang H, Zhou X, Fu D, Le C, Wang J, Zhou Q, Liu X, Yuan Y, Ding K, Xiao Q. Targeting RAS mutants in malignancies: successes, failures, and reasons for hope. Cancer Commun (Lond) 2023; 43:42-74. [PMID: 36316602 PMCID: PMC9859734 DOI: 10.1002/cac2.12377] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/15/2022] [Accepted: 10/13/2022] [Indexed: 01/22/2023] Open
Abstract
RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies. The mutation, isoform (KRAS, HRAS, and NRAS), position, and type of substitution vary depending on the tissue types. Despite decades of developing RAS-targeted therapies, only small subsets of these inhibitors are clinically effective, such as the allele-specific inhibitors against KRASG12C . Targeting the remaining RAS mutants would require further experimental elucidation of RAS signal transduction, RAS-altered metabolism, and the associated immune microenvironment. This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants, including KRAS allele-specific inhibitors, combination therapies, immunotherapies, and metabolism-associated therapies.
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Affiliation(s)
- Hang Yang
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
| | - Xinyi Zhou
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
| | - Dongliang Fu
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
| | - Chenqin Le
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
| | - Jiafeng Wang
- Department of Pharmacology and Department of Gastroenterology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310058P. R. China
| | - Quan Zhou
- Department of Cell BiologySchool of Basic Medical SciencesZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Xiangrui Liu
- Department of Pharmacology and Department of Gastroenterology of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310058P. R. China
- Cancer CenterZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Ying Yuan
- Department of Medical Oncologythe Second Affiliated Hospital of Zhejiang University School of MedicineHangzhouZhejiang310058P. R. China
| | - Kefeng Ding
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
- Cancer CenterZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Qian Xiao
- Department of Colorectal Surgery and OncologyKey Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang310009P. R. China
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12
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Melanogenesis and the Targeted Therapy of Melanoma. Biomolecules 2022; 12:biom12121874. [PMID: 36551302 PMCID: PMC9775438 DOI: 10.3390/biom12121874] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 11/30/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Pigment production is a unique character of melanocytes. Numerous factors are linked with melanin production, including genetics, ultraviolet radiation (UVR) and inflammation. Understanding the mechanism of melanogenesis is crucial to identify new preventive and therapeutic strategies in the treatment of melanoma. Here, we reviewed the current available literatures on the mechanisms of melanogenesis, including the signaling pathways of UVR-induced pigment production, MC1R's central determinant roles and MITF as a master transcriptional regulator in melanogenesis. Moreover, we further highlighted the role of targeting BRAF, NRAS and MC1R in melanoma prevention and treatment. The combination therapeutics of immunotherapy and targeted kinase inhibitors are becoming the newest therapeutic option in advanced melanoma.
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13
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Ferl GZ, Barck KH, Patil J, Jemaa S, Malamut EJ, Lima A, Long JE, Cheng JH, Junttila MR, Carano RA. Automated segmentation of lungs and lung tumors in mouse micro-CT scans. iScience 2022; 25:105712. [PMID: 36582483 PMCID: PMC9792881 DOI: 10.1016/j.isci.2022.105712] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 10/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
Here, we have developed an automated image processing algorithm for segmenting lungs and individual lung tumors in in vivo micro-computed tomography (micro-CT) scans of mouse models of non-small cell lung cancer and lung fibrosis. Over 3000 scans acquired across multiple studies were used to train/validate a 3D U-net lung segmentation model and a Support Vector Machine (SVM) classifier to segment individual lung tumors. The U-net lung segmentation algorithm can be used to estimate changes in soft tissue volume within lungs (primarily tumors and blood vessels), whereas the trained SVM is able to discriminate between tumors and blood vessels and identify individual tumors. The trained segmentation algorithms (1) significantly reduce time required for lung and tumor segmentation, (2) reduce bias and error associated with manual image segmentation, and (3) facilitate identification of individual lung tumors and objective assessment of changes in lung and individual tumor volumes under different experimental conditions.
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Affiliation(s)
- Gregory Z. Ferl
- Preclinical & Translational PKPD, Genentech, South San Francisco, CA 94080, USA,Department of Translational Imaging, Genentech, South San Francisco, CA 94080, USA,Corresponding author
| | - Kai H. Barck
- Department of Translational Imaging, Genentech, South San Francisco, CA 94080, USA,Corresponding author
| | - Jasmine Patil
- Genetic Science Group, Thermo Fisher Scientific, South San Francisco, CA 94080, USA
| | - Skander Jemaa
- Data, Analytics and Imaging, Product Development, Genentech, South San Francisco, CA 94080, USA
| | - Evelyn J. Malamut
- Preclinical & Translational PKPD, Genentech, South San Francisco, CA 94080, USA
| | - Anthony Lima
- Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA
| | - Jason E. Long
- ORIC Pharmaceuticals, South San Francisco, CA 94080, USA
| | - Jason H. Cheng
- Department of Translational Oncology, Genentech, South San Francisco, CA 94080, USA
| | | | - Richard A.D. Carano
- Data, Analytics and Imaging, Product Development, Genentech, South San Francisco, CA 94080, USA
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14
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Jamnongsong S, Kueanjinda P, Buraphat P, Sakornsakolpat P, Vaeteewoottacharn K, Okada S, Jirawatnotai S, Sampattavanich S. Comprehensive drug response profiling and pan-omic analysis identified therapeutic candidates and prognostic biomarkers for Asian cholangiocarcinoma. iScience 2022; 25:105182. [PMID: 36248745 PMCID: PMC9563539 DOI: 10.1016/j.isci.2022.105182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/11/2022] [Accepted: 09/20/2022] [Indexed: 11/12/2022] Open
Abstract
Cholangiocarcinoma (CCA) is rare cancer with the highest incidence in Eastern and Southeast Asian countries. Advanced CCA patients rely on chemotherapeutic regimens that offer unsatisfied clinical outcomes. We developed a comprehensive drug response profiling to investigate potential new drugs using CCA cell lines from Thai and Japanese patients against 100 approved anti-cancer drugs. We identified two major CCA subgroups that displayed unique molecular pathways from our integrative pan-omic and ligand-induced pathway activation analyses. MEK and Src inhibitors specifically killed the CCA1 subgroup without causing cytotoxicity to the normal cholangiocyte. Next, we developed the CCA45 signature to classify CCA patients based on their transcriptomic data. Our CCA45 signature could accurately predict prognosis, especially for Asian CCA patients. Our study provides a comprehensive public resource for drug repurposing in CCA and introduces analytical strategies for prioritizing cancer therapeutic agents for other rare cancer.
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Affiliation(s)
- Supawan Jamnongsong
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Patipark Kueanjinda
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pongsakorn Buraphat
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Phuwanat Sakornsakolpat
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | | | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
| | - Siwanon Jirawatnotai
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Somponnat Sampattavanich
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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15
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Wang Q, Feng J, Tang L. Non-Coding RNA Related to MAPK Signaling Pathway in Liver Cancer. Int J Mol Sci 2022; 23:11908. [PMID: 36233210 PMCID: PMC9570382 DOI: 10.3390/ijms231911908] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022] Open
Abstract
The advancement in high-throughput sequencing analysis and the evaluation of chromatin state maps have revealed that eukaryotic cells produce many non-coding transcripts/RNAs. Further, a strong association was observed between some non-coding RNAs and cancer development. The mitogen-activated protein kinases (MAPK) belong to the serine-threonine kinase family and are the primary signaling pathways involved in cell proliferation from the cell surface to the nucleus. They play an important role in various human diseases. A few non-coding RNAs associated with the MAPK signaling pathway play a significant role in the development of several malignancies, including liver cancer. In this review, we summarize the molecular mechanisms and interactions of microRNA, lncRNA, and other non-coding RNAs in the development of liver cancer that are associated with the MAPK signaling pathway. Further, we briefly discuss the therapeutic strategies for liver cancer related to ncRNA and the MAPK signaling pathway.
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Affiliation(s)
- Qiuxia Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Jianguo Feng
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
- Laboratory of Anesthesiology, Southwest Medical University, Luzhou 646000, China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
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16
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Lin L, Miao L, Lin H, Cheng J, Li M, Zhuo Z, He J. Targeting RAS in neuroblastoma: Is it possible? Pharmacol Ther 2022; 236:108054. [PMID: 34915055 DOI: 10.1016/j.pharmthera.2021.108054] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 12/06/2021] [Accepted: 12/08/2021] [Indexed: 02/07/2023]
Abstract
Neuroblastoma is a common solid tumor in children and a leading cause of cancer death in children. Neuroblastoma exhibits genetic, morphological, and clinical heterogeneity that limits the efficacy of current monotherapies. With further research on neuroblastoma, the pathogenesis of neuroblastoma is found to be complex, and more and more treatment therapies are needed. The importance of personalized therapy is growing. Currently, various molecular features, including RAS mutations, are being used as targets for the development of new therapies for patients with neuroblastoma. A recent study found that RAS mutations are frequently present in recurrent neuroblastoma. RAS mutations have been shown to activate the MAPK pathway and play an important role in neuroblastoma. Treating RAS mutated neuroblastoma is a difficult challenge, but many preclinical studies have yielded effective results. At the same time, many of the therapies used to treat RAS mutated tumors also have good reference values for treating RAS mutated neuroblastoma. The success of KRAS-G12C inhibitors has greatly stimulated confidence in the direct suppression of RAS. This review describes the biological role of RAS and the frequency of RAS mutations in neuroblastoma. This paper focuses on the strategies, preclinical, and clinical progress of targeting carcinogenic RAS in neuroblastoma, and proposes possible prospects and challenges in the future.
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Affiliation(s)
- Lei Lin
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Lei Miao
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Huiran Lin
- Faculty of Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Jiwen Cheng
- Department of Pediatric Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China
| | - Meng Li
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Zhenjian Zhuo
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China; Laboratory Animal Center, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China.
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17
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Tumor Molecular Profiling in Hispanics: Moving Towards Precision Oncology and Health Equity. J Racial Ethn Health Disparities 2022; 10:1423-1431. [PMID: 35648382 PMCID: PMC10163076 DOI: 10.1007/s40615-022-01328-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 05/04/2022] [Accepted: 05/05/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Tumor molecular profiling techniques, such as next-generation sequencing (NGS) to identify somatic genetic alterations, allow physicians to have a better understanding of the affected carcinogenic pathways and guide targeted therapy. The objective of our study was to characterize common somatic alterations and carcinogenic pathways among Puerto Rican Hispanics with solid tumors. METHODS We conducted a single-institution, retrospective study to characterize molecular tumor profiles using a 592-gene NGS platform. Actionable mutations with current or developing therapies targeting affected genes/pathways were highlighted. RESULTS Tumors from 50 Hispanic patients were evaluated using CARIS Life Science© NGS testing. The median age of our study population was 55 (range 21-84); 54% (n = 27) were males. The primary tumor sites were colorectal (n = 24), gastric (n = 5), breast (n = 4), and lung (n = 3). The most common genetic mutations identified were in TP53 (44%), APC (38%), and KRAS (32%); followed by alterations in EGFR (4%), HER2 (6%), and homologous recombinant deficiency genes (BRCA2, 6%). Genetic alterations were found in multiple signaling pathways particularly in the cell cycle control pathway, MAPK and Wnt/β-Catenin signaling pathways. Targetable biomarkers were identified in 27/50 (54.0%) of tumors. DISCUSSION Molecular profiling techniques, such as next-generation sequencing, have substantially expanded access to alterations in the cancer genome. Our findings demonstrated important actionable mutations in most of the tumors evaluated and support the integration of somatic mutation profiling in the evaluation of Hispanic cancer patients with advanced cancer to help guide therapeutic options.
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18
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Conroy M, Cowzer D, Kolch W, Duffy AG. Emerging RAS-directed therapies for cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 4:543-558. [PMID: 35582302 PMCID: PMC9094076 DOI: 10.20517/cdr.2021.07] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/08/2021] [Accepted: 03/16/2021] [Indexed: 12/12/2022]
Abstract
RAS oncogenes are the most commonly mutated oncogenes in human cancer, and RAS-mutant cancers represent a major burden of human disease. Though these oncogenes were discovered decades ago, recent years have seen major advances in understanding of their structure and function, including the therapeutic and prognostic significance of diverse isoforms. Targeting of these mutations has proven difficult, despite some successes with inhibition of RAS effector signalling. More recently, direct RAS inhibition has been achieved in a trial setting. While this has yet to be translated to everyday clinical practice, this development carries much promise. This review summarizes the diverse approaches that have been taken to RAS inhibition and then focuses on the most recent developments in direct inhibition of KRAS(G12C).
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Affiliation(s)
- Michael Conroy
- Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin 7, Ireland.,Authors contributed equally
| | - Darren Cowzer
- Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin 7, Ireland.,Authors contributed equally
| | - Walter Kolch
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.,Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
| | - Austin G Duffy
- Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin 7, Ireland
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19
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Park HB, Baek KH. E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers. Biochim Biophys Acta Rev Cancer 2022; 1877:188736. [DOI: 10.1016/j.bbcan.2022.188736] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/30/2022] [Accepted: 05/11/2022] [Indexed: 12/13/2022]
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20
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Diehl JN, Hibshman PS, Ozkan-Dagliyan I, Goodwin CM, Howard SV, Cox AD, Der CJ. Targeting the ERK mitogen-activated protein kinase cascade for the treatment of KRAS-mutant pancreatic cancer. Adv Cancer Res 2022; 153:101-130. [PMID: 35101228 DOI: 10.1016/bs.acr.2021.07.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Mutational activation of the KRAS oncogene is found in ~95% of pancreatic ductal adenocarcinoma (PDAC), the major form of pancreatic cancer. With substantial experimental evidence that continued aberrant KRAS function is essential for the maintenance of PDAC tumorigenic growth, the National Cancer Institute has identified the development of effective anti-KRAS therapies as one of four major initiatives for pancreatic cancer research. The recent clinical success in the development of an anti-KRAS therapy targeting one specific KRAS mutant (G12C) supports the significant potential impact of anti-KRAS therapies. However, KRASG12C mutations comprise only 2% of KRAS mutations in PDAC. Thus, there remains a dire need for additional therapeutic approaches for targeting the majority of KRAS-mutant PDAC. Among the different directions currently being pursued for anti-KRAS drug development, one of the most promising involves inhibitors of the key KRAS effector pathway, the three-tiered RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. We address the promises and challenges of targeting ERK MAPK signaling as an anti-KRAS therapy for PDAC. In particular, we also summarize the key role of the MYC transcription factor and oncoprotein in supporting ERK-dependent growth of KRAS-mutant PDAC.
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Affiliation(s)
- J Nathaniel Diehl
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Priya S Hibshman
- Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Irem Ozkan-Dagliyan
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Craig M Goodwin
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Sarah V Howard
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Adrienne D Cox
- Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Channing J Der
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
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21
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Winkler M, Friedrich J, Boedicker C, Dolgikh N. Co-targeting MCL-1 and ERK1/2 kinase induces mitochondrial apoptosis in rhabdomyosarcoma cells. Transl Oncol 2022; 16:101313. [PMID: 34906889 PMCID: PMC8681038 DOI: 10.1016/j.tranon.2021.101313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 01/17/2023] Open
Abstract
The RAS/MEK/ERK genetic axis is commonly altered in rhabdomyosarcoma (RMS), indicating high activity of downstream effector ERK1/2 kinase. Previously, we have demonstrated that inhibition of the RAS/MEK/ERK signaling pathway in RMS is insufficient to induce cell death due to residual pro-survival MCL-1 activity. Here, we show that the combination of ERK1/2 inhibitor Ulixertinib and MCL-1 inhibitor S63845 is highly synergistic and induces apoptotic cell death in RMS in vitro and in vivo. Importantly, Ulixertinib/S63845 co-treatment suppresses long-term survival of RMS cells, induces rapid caspase activation and caspase-dependent apoptosis. Mechanistically, Ulixertinib-mediated upregulation of BIM and BMF in combination with MCL-1 inhibition by S63845 shifts the balance of BCL-2 proteins towards a pro-apoptotic state resulting in apoptosis induction. A genetic silencing approach reveals that BIM, BMF, BAK and BAX are all required for Ulixertinib/S63845-induced apoptosis. Overexpression of BCL-2 rescues cell death triggered by Ulixertinib/S63845 co-treatment, confirming that combined inhibition of ERK1/2 and MCL-1 effectively induces cell death of RMS cells via the intrinsic mitochondrial apoptotic pathway. Thus, this study is the first to demonstrate the cytotoxic potency of co-inhibition of ERK1/2 and MCL-1 for RMS treatment.
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Affiliation(s)
- Marius Winkler
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528 Frankfurt, Germany
| | - Juliane Friedrich
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528 Frankfurt, Germany
| | - Cathinka Boedicker
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528 Frankfurt, Germany
| | - Nadezda Dolgikh
- Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528 Frankfurt, Germany.
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22
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Tatli O, Dinler Doganay G. Recent Developments in Targeting RAS Downstream Effectors for RAS-Driven Cancer Therapy. Molecules 2021; 26:molecules26247561. [PMID: 34946644 PMCID: PMC8703923 DOI: 10.3390/molecules26247561] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022] Open
Abstract
Aberrant activity of oncogenic rat sarcoma virus (RAS) protein promotes tumor growth and progression. RAS-driven cancers comprise more than 30% of all human cancers and are refractory to frontline treatment strategies. Since direct targeting of RAS has proven challenging, efforts have been centered on the exploration of inhibitors for RAS downstream effector kinases. Two major RAS downstream signaling pathways, including the Raf/MEK/Erk cascade and the phosphatidylinositol-3-kinase (PI3K) pathway, have become compelling targets for RAS-driven cancer therapy. However, the main drawback in the blockade of a single RAS effector is the multiple levels of crosstalk and compensatory mechanisms between these two pathways that contribute to drug resistance against monotherapies. A growing body of evidence reveals that the sequential or synergistic inhibition of multiple RAS effectors is a more convenient route for the efficacy of cancer therapy. Herein, we revisit the recent developments and discuss the most promising modalities targeting canonical RAS downstream effectors for the treatment of RAS-driven cancers.
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Affiliation(s)
- Ozge Tatli
- Department of Molecular Biology, Genetics-Biotechnology, Graduate School, Istanbul Technical University, Istanbul 34469, Turkey;
- Department of Molecular Biology and Genetics, Istanbul Medeniyet University, Istanbul 34720, Turkey
| | - Gizem Dinler Doganay
- Department of Molecular Biology, Genetics-Biotechnology, Graduate School, Istanbul Technical University, Istanbul 34469, Turkey;
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
- Correspondence: ; Tel.: +90-2122-857-256
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23
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Errington TM, Denis A, Allison AB, Araiza R, Aza-Blanc P, Bower LR, Campos J, Chu H, Denson S, Donham C, Harr K, Haven B, Iorns E, Kwok J, McDonald E, Pelech S, Perfito N, Pike A, Sampey D, Settles M, Scott DA, Sharma V, Tolentino T, Trinh A, Tsui R, Willis B, Wood J, Young L. Experiments from unfinished Registered Reports in the Reproducibility Project: Cancer Biology. eLife 2021; 10:73430. [PMID: 34874009 PMCID: PMC8651290 DOI: 10.7554/elife.73430] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/14/2021] [Indexed: 12/16/2022] Open
Abstract
As part of the Reproducibility Project: Cancer Biology, we published Registered Reports that described how we intended to replicate selected experiments from 29 high-impact preclinical cancer biology papers published between 2010 and 2012. Replication experiments were completed and Replication Studies reporting the results were submitted for 18 papers, of which 17 were accepted and published by eLife with the rejected paper posted as a preprint. Here, we report the status and outcomes obtained for the remaining 11 papers. Four papers initiated experimental work but were stopped without any experimental outcomes. Two papers resulted in incomplete outcomes due to unanticipated challenges when conducting the experiments. For the remaining five papers only some of the experiments were completed with the other experiments incomplete due to mundane technical or unanticipated methodological challenges. The experiments from these papers, along with the other experiments attempted as part of the Reproducibility Project: Cancer Biology, provides evidence about the challenges of repeating preclinical cancer biology experiments and the replicability of the completed experiments.
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Affiliation(s)
| | | | - Anne B Allison
- Piedmont Virginia Community College, Charlottesville, United States
| | - Renee Araiza
- University of California, Davis, Davis, United States
| | | | | | | | - Heidi Chu
- Applied Biological Materials, Richmond, Canada
| | - Sarah Denson
- University of California, Davis, Davis, United States
| | | | - Kaitlyn Harr
- University of Virginia, Charlottesville, United States
| | | | | | - Jennie Kwok
- Applied Biological Materials, Richmond, Canada
| | - Elysia McDonald
- Drexel University College of Medicine, Philadelphia, United States
| | - Steven Pelech
- Kinexus Bioinformatics, Vancouver, Canada.,University of British Columbia, Vancouver, United States
| | | | - Amanda Pike
- Applied Biological Materials, Richmond, Canada
| | | | | | - David A Scott
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
| | | | | | | | | | | | - Joshua Wood
- University of California, Davis, Davis, United States
| | - Lisa Young
- Applied Biological Materials, Richmond, Canada
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24
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Enhancing the Therapeutic Efficacy of KRAS G12C Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90. JOURNAL OF ONCOLOGY 2021; 2021:2721466. [PMID: 34858498 PMCID: PMC8632397 DOI: 10.1155/2021/2721466] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/29/2021] [Indexed: 02/08/2023]
Abstract
Background KRASG12C inhibitors have shown promising efficacy in early clinical trials, but drug resistance compromises their long-term benefits. Therefore, it is critical to understand the mechanisms of drug resistance and to design appropriate combinatory treatments to improve efficacy. Methods To understand the comprehensive mechanisms of drug resistance, we treated lung cancer cells with KRASG12C inhibitors for different periods and performed transcriptional profiling and signaling analysis to identify critical factors and pathways that drive drug tolerance and resistance. We also evaluated several drug combinations in vitro and in vivo to identify potentially effective therapeutics. Results We found that the feedback activation of multiple receptor tyrosine kinases (RTKs) may have cooperatively induced intrinsic and adaptive resistance to KRASG12C inhibitors. Notably, continuous KRAS inhibition induced a multidrug-resistant phenotype, implying that upfront combinatory treatment might be required to treat this group of patients. We also demonstrated that concurrently targeting multiple nodes in the RTK/RAS/RAF/MEK/ERK axis improved the efficacy of KRASG12C inhibitors, mainly by suppressing the reactivation of the mitogen-activated protein kinase (MAPK) pathway. Moreover, the combined use of HSP90 and KRASG12C inhibitors effectively induced tumor regression in lung adenocarcinoma models in vitro and in vivo. Conclusion Together, our findings revealed mechanisms underlying KRASG12C inhibitors resistance and provided novel candidate combinatory strategies to improve their anticancer activity.
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25
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Stochasticity and positive feedback enable enzyme kinetics at the membrane to sense reaction size. Proc Natl Acad Sci U S A 2021; 118:2103626118. [PMID: 34789575 PMCID: PMC8617498 DOI: 10.1073/pnas.2103626118] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/10/2021] [Indexed: 12/27/2022] Open
Abstract
Cellular membranes span a wide range of spatial dimensions, from the plasma membrane with a scale of microns to vesicles on the nanometer scale. The work presented here identifies a molecular mechanism, based on common features of cellular signaling enzymes, that causes the average enzymatic catalytic rate to exhibit reaction size dependency. This effect stems from stochastic variation, but the final results can be essentially deterministic. In competitive enzymatic reaction cycles, the final product can depend on the size of the reaction system. The simplicity of the mechanism suggests that size-dependent reaction rates may be widespread among signaling enzymes and thus enable reaction size to be an important factor in signal regulation at the membrane. Here, we present detailed kinetic analyses of a panel of soluble lipid kinases and phosphatases, as well as Ras activating proteins, acting on their respective membrane surface substrates. The results reveal that the mean catalytic rate of such interfacial enzymes can exhibit a strong dependence on the size of the reaction system—in this case membrane area. Experimental measurements and kinetic modeling reveal how stochastic effects stemming from low molecular copy numbers of the enzymes alter reaction kinetics based on mechanistic characteristics of the enzyme, such as positive feedback. For the competitive enzymatic cycles studied here, the final product—consisting of a specific lipid composition or Ras activity state—depends on the size of the reaction system. Furthermore, we demonstrate how these reaction size dependencies can be controlled by engineering feedback mechanisms into the enzymes.
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26
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Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Mol Cancer 2021; 20:143. [PMID: 34742312 PMCID: PMC8571891 DOI: 10.1186/s12943-021-01441-4] [Citation(s) in RCA: 221] [Impact Index Per Article: 55.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/04/2021] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.
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27
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Garcia N, Del Pozo V, Yohe ME, Goodwin CM, Shackleford TJ, Wang L, Baxi K, Chen Y, Rogojina AT, Zimmerman SM, Peer CJ, Figg WD, Ignatius MS, Wood KC, Houghton PJ, Vaseva AV. Vertical Inhibition of the RAF-MEK-ERK Cascade Induces Myogenic Differentiation, Apoptosis and Tumor Regression in H/NRAS Q61X-mutant Rhabdomyosarcoma. Mol Cancer Ther 2021; 21:170-183. [PMID: 34737198 PMCID: PMC8742779 DOI: 10.1158/1535-7163.mct-21-0194] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 08/18/2021] [Accepted: 11/02/2021] [Indexed: 11/16/2022]
Abstract
Oncogenic RAS signaling is an attractive target for fusion-negative rhabdomyosarcoma (FN-RMS). Our study validates the role of the ERK MAPK effector pathway in mediating RAS dependency in a panel of H/NRASQ61X-mutant RMS cells and correlates in vivo efficacy of the MEK inhibitor trametinib with pharmacodynamics of ERK activity. A screen is used to identify trametinib-sensitizing targets and combinations are evaluated in cells and tumor xenografts. We find that the ERK MAPK pathway is central to H/NRASQ61X-dependency in RMS cells, however there is poor in vivo response to clinically relevant exposures with trametinib, which correlates with inefficient suppression of ERK activity. CRISPR screening points to vertical inhibition of the RAF-MEK-ERK cascade by co-suppression of MEK and either CRAF or ERK. CRAF is central to rebound pathway activation following MEK or ERK inhibition. Concurrent CRAF suppression and MEK or ERK inhibition, or concurrent pan-RAF and MEK/ERK inhibition (pan-RAFi + MEKi/ERKi), or concurrent MEK and ERK inhibition (MEKi + ERKi) all synergistically block ERK activity and induce myogenic differentiation and apoptosis. In vivo assessment of pan-RAFi + ERKi or MEKi + ERKi potently suppress growth of H/NRASQ61X RMS tumor xenografts, with pan-RAFi + ERKi being more effective and better tolerated. We conclude that CRAF reactivation limits the activity of single agent MEK/ERK inhibitors in FN-RMS. Vertical targeting of the RAF-MEK-ERK cascade, and particularly co-targeting of CRAF and MEK or ERK, or the combination of pan-RAF inhibitors with MEK or ERK inhibitors, have synergistic activity and potently suppress H/NRASQ61X-mutant RMS tumor growth.
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Affiliation(s)
| | | | | | - Craig M Goodwin
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
| | | | - Long Wang
- Cancer Therapy & Research Center, The University of Texas Health Science Center
| | - Kunal Baxi
- Greehey Children's Cancer Research Institute, UTHSCSA
| | - Yidong Chen
- Department of Population Health Sciences, The University of Texas Health Science Center at San Antonio
| | | | | | - Cody J Peer
- Clinical Pharmacology Program, National Cancer Institute
| | - William D Figg
- Clinical Pharmacology Program and Genitourinary Malignancies Branch, National Cancer Institute
| | | | - Kris C Wood
- Department of Pharmacology and Cancer Biology, Duke University
| | - Peter J Houghton
- Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio
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28
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KRASG12C inhibitor: combing for combination. Biochem Soc Trans 2021; 48:2691-2701. [PMID: 33242077 DOI: 10.1042/bst20200473] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022]
Abstract
Oncogenic mutation in KRAS is one of the most common alterations in human cancer. After decades of extensive research and unsuccessful drug discovery programs, therapeutic targeting of KRAS mutant tumour is at an exciting juncture. The discovery of mutation-specific inhibitors of KRASG12C and early positive findings from clinical trials has raised the hope of finally having a drug to treat a significant segment of KRAS mutant cancer patients. Crucially, it has also re-energized the RAS field to look beyond G12C mutation and find new innovative targeting opportunities. However, the early clinical trial data also indicates that there is significant variation in response among patients and that monotherapy treatment with KRASG12C inhibitors (G12Ci) alone is unlikely to be sufficient to elicit a sustained response. Understanding the molecular mechanism of variation in patient response and identifying possible combination opportunities, which could be exploited to achieve durable and significant responses and delay emergence of resistance, is central to the success of G12Ci therapy. Given the specificity of G12Ci, toxicity is expected to be minimal. Therefore, it might be possible to combine G12Ci with other targeted agents which have previously been explored to tackle KRAS mutant cancer but deemed too toxic, e.g. MEK inhibitor. Ongoing clinical trials will shed light on clinical resistance to G12C inhibitors, however extensive work is already ongoing to identify the best combination partners. This review provides an update on combination opportunities which could be explored to maximize the benefit of this new exciting drug.
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Wang WH, Yuan T, Qian MJ, Yan FJ, Yang L, He QJ, Yang B, Lu JJ, Zhu H. Post-translational modification of KRAS: potential targets for cancer therapy. Acta Pharmacol Sin 2021; 42:1201-1211. [PMID: 33087838 PMCID: PMC8285426 DOI: 10.1038/s41401-020-00542-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 09/16/2020] [Indexed: 02/02/2023]
Abstract
Aberrant activation of the RAS superfamily is one of the critical factors in carcinogenesis. Among them, KRAS is the most frequently mutated one which has inspired extensive studies for developing approaches to intervention. Although the cognition toward KRAS remains far from complete, mounting evidence suggests that a variety of post-translational modifications regulate its activation and localization. In this review, we summarize the regulatory mode of post-translational modifications on KRAS including prenylation, post-prenylation, palmitoylation, ubiquitination, phosphorylation, SUMOylation, acetylation, nitrosylation, etc. We also highlight the recent studies targeting these modifications having exhibited potent anti-tumor activities.
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Affiliation(s)
- Wei-Hua Wang
- Zhejiang Province Key Laboratory of Anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Tao Yuan
- Zhejiang Province Key Laboratory of Anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Mei-Jia Qian
- Zhejiang Province Key Laboratory of Anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Fang-Jie Yan
- Zhejiang Province Key Laboratory of Anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Liu Yang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China
| | - Qiao-Jun He
- Zhejiang Province Key Laboratory of Anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jin-Jian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
| | - Hong Zhu
- Zhejiang Province Key Laboratory of Anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
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Molina-Arcas M, Samani A, Downward J. Drugging the Undruggable: Advances on RAS Targeting in Cancer. Genes (Basel) 2021; 12:899. [PMID: 34200676 PMCID: PMC8228461 DOI: 10.3390/genes12060899] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/02/2021] [Accepted: 06/04/2021] [Indexed: 12/19/2022] Open
Abstract
Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its 'switch-II pocket' have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designed to overcome primary resistance and extend durability of response. Finally, we briefly discuss novel approaches to targeting non-G12C mutant isoforms.
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Affiliation(s)
| | - Amit Samani
- Oncogene Biology Laboratory, Francis Crick Institute, London NW1 1AT, UK;
- Department of Medical Oncology, Imperial College Healthcare NHS Trust, London W2 1NY, UK
| | - Julian Downward
- Oncogene Biology Laboratory, Francis Crick Institute, London NW1 1AT, UK;
- Lung Cancer Group, Institute of Cancer Research, London SW3 6JB, UK
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NRAS mutant melanoma: Towards better therapies. Cancer Treat Rev 2021; 99:102238. [PMID: 34098219 DOI: 10.1016/j.ctrv.2021.102238] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 12/24/2022]
Abstract
Genetic alterations affecting RAS proteins are commonly found in human cancers. Roughly a fourth of melanoma patients carry activating NRAS mutations, rendering this malignancy particularly challenging to treat. Although the development of targeted as well as immunotherapies led to a substantial improvement in the overall survival of non-NRASmut melanoma patients (e.g. BRAFmut), patients with NRASmut melanomas have an overall poorer prognosis due to the high aggressiveness of RASmut tumors, lack of efficient targeted therapies or rapidly emerging resistance to existing treatments. Understanding how NRAS-driven melanomas develop therapy resistance by maintaining cell cycle progression and survival is crucial to develop more effective and specific treatments for this group of melanoma patients. In this review, we provide an updated summary of currently available therapeutic options for NRASmut melanoma patients with a focus on combined inhibition of MAPK signaling and CDK4/6-driven cell cycle progression and mechanisms of the inevitably developing resistance to these treatments. We conclude with an outlook on the most promising novel therapeutic approaches for melanoma patients with constitutively active NRAS. STATEMENT OF SIGNIFICANCE: An estimated 75000 patients are affected by NRASmut melanoma each year and these patients still have a shorter progression-free survival than BRAFmut melanomas. Both intrinsic and acquired resistance occur in NRAS-driven melanomas once treated with single or combined targeted therapies involving MAPK and CDK4/6 inhibitors and/or checkpoint inhibiting immunotherapy. Oncolytic viruses, mRNA-based vaccinations, as well as targeted triple-agent therapy are promising alternatives, which could soon contribute to improved progression-free survival of the NRASmut melanoma patient group.
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Catalano A, Adlesic M, Kaltenbacher T, Klar RFU, Albers J, Seidel P, Brandt LP, Hejhal T, Busenhart P, Röhner N, Zodel K, Fritsch K, Wild PJ, Duyster J, Fritsch R, Brummer T, Frew IJ. Sensitivity and Resistance of Oncogenic RAS-Driven Tumors to Dual MEK and ERK Inhibition. Cancers (Basel) 2021; 13:cancers13081852. [PMID: 33924486 PMCID: PMC8069437 DOI: 10.3390/cancers13081852] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/03/2021] [Accepted: 04/07/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Mutations in RAS-family genes frequently cause different types of human cancers. Inhibitors of the MEK (mitogen-activated protein kinase) and ERK (extracellular signal-regulated kinase) protein kinases that function downstream of RAS proteins have shown some clinical benefits when used for the treatment of these cancers, but drug resistance frequently emerges. Here we show that combined treatment with MEK and ERK inhibitors blocks the emergence of resistance to either drug alone. However, if cancer cells have already developed resistance to MEK inhibitors or to ERK inhibitors, the combined therapy is frequently ineffective. These findings imply that these inhibitors should be used together for cancer therapy. We also show that drug resistance involves complex patterns of rewiring of cellular kinase signaling networks that do not overlap between each different cancer cell line. Nonetheless, we show that MAP4K4 is required for efficient cell proliferation in several different MEK/ERK inhibitor resistant cancer cell lines, uncovering a potential new therapeutic target. Abstract Oncogenic mutations in RAS family genes arise frequently in metastatic human cancers. Here we developed new mouse and cellular models of oncogenic HrasG12V-driven undifferentiated pleomorphic sarcoma metastasis and of KrasG12D-driven pancreatic ductal adenocarcinoma metastasis. Through analyses of these cells and of human oncogenic KRAS-, NRAS- and BRAF-driven cancer cell lines we identified that resistance to single MEK inhibitor and ERK inhibitor treatments arise rapidly but combination therapy completely blocks the emergence of resistance. The prior evolution of resistance to either single agent frequently leads to resistance to dual treatment. Dual MEK inhibitor plus ERK inhibitor therapy shows anti-tumor efficacy in an HrasG12V-driven autochthonous sarcoma model but features of drug resistance in vivo were also evident. Array-based kinome activity profiling revealed an absence of common patterns of signaling rewiring in single or double MEK and ERK inhibitor resistant cells, showing that the development of resistance to downstream signaling inhibition in oncogenic RAS-driven tumors represents a heterogeneous process. Nonetheless, in some single and double MEK and ERK inhibitor resistant cell lines we identified newly acquired drug sensitivities. These may represent additional therapeutic targets in oncogenic RAS-driven tumors and provide general proof-of-principle that therapeutic vulnerabilities of drug resistant cells can be identified.
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Affiliation(s)
- Antonella Catalano
- Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.C.); (M.A.); (R.F.U.K.); (P.S.); (N.R.); (K.Z.); (K.F.); (J.D.); (R.F.)
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.A.); (L.P.B.); (T.H.); (P.B.)
- Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland
- Signaling Research Centre BIOSS, University of Freiburg, 79104 Freiburg, Germany;
| | - Mojca Adlesic
- Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.C.); (M.A.); (R.F.U.K.); (P.S.); (N.R.); (K.Z.); (K.F.); (J.D.); (R.F.)
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.A.); (L.P.B.); (T.H.); (P.B.)
- Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland
- Signaling Research Centre BIOSS, University of Freiburg, 79104 Freiburg, Germany;
| | - Thorsten Kaltenbacher
- Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany;
| | - Rhena F. U. Klar
- Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.C.); (M.A.); (R.F.U.K.); (P.S.); (N.R.); (K.Z.); (K.F.); (J.D.); (R.F.)
- Spemann Graduate School of Biology and Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Joachim Albers
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.A.); (L.P.B.); (T.H.); (P.B.)
- Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland
| | - Philipp Seidel
- Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.C.); (M.A.); (R.F.U.K.); (P.S.); (N.R.); (K.Z.); (K.F.); (J.D.); (R.F.)
- Signaling Research Centre BIOSS, University of Freiburg, 79104 Freiburg, Germany;
| | - Laura P. Brandt
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.A.); (L.P.B.); (T.H.); (P.B.)
- Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland
| | - Tomas Hejhal
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.A.); (L.P.B.); (T.H.); (P.B.)
- Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland
| | - Philipp Busenhart
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.A.); (L.P.B.); (T.H.); (P.B.)
- Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland
| | - Niklas Röhner
- Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.C.); (M.A.); (R.F.U.K.); (P.S.); (N.R.); (K.Z.); (K.F.); (J.D.); (R.F.)
| | - Kyra Zodel
- Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.C.); (M.A.); (R.F.U.K.); (P.S.); (N.R.); (K.Z.); (K.F.); (J.D.); (R.F.)
- Signaling Research Centre BIOSS, University of Freiburg, 79104 Freiburg, Germany;
| | - Kornelia Fritsch
- Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.C.); (M.A.); (R.F.U.K.); (P.S.); (N.R.); (K.Z.); (K.F.); (J.D.); (R.F.)
| | - Peter J. Wild
- Department of Pathology and Molecular Pathology, University Hospital Zurich, 8006 Zurich, Switzerland;
| | - Justus Duyster
- Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.C.); (M.A.); (R.F.U.K.); (P.S.); (N.R.); (K.Z.); (K.F.); (J.D.); (R.F.)
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Ralph Fritsch
- Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.C.); (M.A.); (R.F.U.K.); (P.S.); (N.R.); (K.Z.); (K.F.); (J.D.); (R.F.)
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Hematology and Medical Oncology, University Hospital of Zurich, 8006 Zurich, Switzerland
| | - Tilman Brummer
- Signaling Research Centre BIOSS, University of Freiburg, 79104 Freiburg, Germany;
- Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany;
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Ian J. Frew
- Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.C.); (M.A.); (R.F.U.K.); (P.S.); (N.R.); (K.Z.); (K.F.); (J.D.); (R.F.)
- Institute of Physiology, University of Zurich, 8057 Zurich, Switzerland; (J.A.); (L.P.B.); (T.H.); (P.B.)
- Zurich Center for Integrative Human Physiology, University of Zurich, 8006 Zurich, Switzerland
- Signaling Research Centre BIOSS, University of Freiburg, 79104 Freiburg, Germany;
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Correspondence: ; Tel.: +49-761-270-71831
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Herrick WG, Kilpatrick CL, Hollingshead MG, Esposito D, O'Sullivan Coyne G, Gross AM, Johnson BC, Chen AP, Widemann BC, Doroshow JH, Parchment RE, Srivastava AK. Isoform- and Phosphorylation-specific Multiplexed Quantitative Pharmacodynamics of Drugs Targeting PI3K and MAPK Signaling in Xenograft Models and Clinical Biopsies. Mol Cancer Ther 2021; 20:749-760. [PMID: 33536190 PMCID: PMC8026683 DOI: 10.1158/1535-7163.mct-20-0566] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/16/2020] [Accepted: 02/01/2021] [Indexed: 11/16/2022]
Abstract
Ras/Raf/MEK/ERK (MAPK) and PI3K/AKT signaling pathways influence several cell functions involved in oncogenesis, making them attractive drug targets. We describe a novel multiplex immunoassay to quantitate isoform-specific phosphorylation of proteins in the PI3K/AKT and MAPK pathways as a tool to assess pharmacodynamic changes. Isoform-specific assays measuring total protein and site-specific phosphorylation levels of ERK1/2, MEK1/2, AKT1/2/3, and rpS6 were developed on the Luminex platform with validated antibody reagents. The multiplex assay demonstrated satisfactory analytic performance. Fit-for-purpose validation was performed with xenograft models treated with selected agents. In PC3 and HCC70 xenograft tumors, the PI3Kβ inhibitor AZD8186 suppressed phosphorylation of AKT1, AKT2, and rpS6 for 4 to 7 hours post single dose, but levels returned to baseline by 24 hours. AKT3 phosphorylation was suppressed in PC3 xenografts at all doses tested, but only at the highest dose in HCC70. The AKT inhibitor MK-2206 reduced AKT1/2/3 phosphorylation in SW620 xenograft tumors 2 to 4 hours postdose, and the MEK inhibitor selumetinib reduced MEK1/2 and ERK1/2 phosphorylation by up to 50% and >90%, respectively. Clinical utility was demonstrated by analyzing biopsies from untreated patients with plexiform neurofibromas enrolled in a clinical trial of selumetinib (NCT02407405). These biopsies showed MEK and ERK phosphorylation levels sufficient for measuring up to 90% inhibition, and low AKT and rpS6 phosphorylation. This validated multiplex immunoassay demonstrates the degree and duration of phosphorylation modulation for three distinct classes of drugs targeting the PI3K/AKT and MAPK pathways.
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Affiliation(s)
- William G Herrick
- Clinical Pharmacodynamics Biomarker Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Casey L Kilpatrick
- Clinical Pharmacodynamics Biomarker Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | | | - Dominic Esposito
- Protein Expression Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | | | - Andrea M Gross
- Pediatric Oncology Branch, NCI, Bethesda, Maryland
- Center for Cancer Research, NCI, Bethesda, Maryland
| | - Barry C Johnson
- Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
| | - Alice P Chen
- Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
| | - Brigitte C Widemann
- Pediatric Oncology Branch, NCI, Bethesda, Maryland
- Center for Cancer Research, NCI, Bethesda, Maryland
| | - James H Doroshow
- Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
- Center for Cancer Research, NCI, Bethesda, Maryland
| | - Ralph E Parchment
- Clinical Pharmacodynamics Biomarker Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Apurva K Srivastava
- Clinical Pharmacodynamics Biomarker Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
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Ottaviano M, Giunta EF, Tortora M, Curvietto M, Attademo L, Bosso D, Cardalesi C, Rosanova M, De Placido P, Pietroluongo E, Riccio V, Mucci B, Parola S, Vitale MG, Palmieri G, Daniele B, Simeone E, on behalf of SCITO YOUTH. BRAF Gene and Melanoma: Back to the Future. Int J Mol Sci 2021; 22:ijms22073474. [PMID: 33801689 PMCID: PMC8037827 DOI: 10.3390/ijms22073474] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 03/20/2021] [Accepted: 03/22/2021] [Indexed: 12/13/2022] Open
Abstract
As widely acknowledged, 40-50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS-RAF-MEK-ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.
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Affiliation(s)
- Margaret Ottaviano
- Department of Clinical Medicine and Surgery, Università Degli Studi di Napoli “Federico II”, 80131 Naples, Italy; (P.D.P.); (E.P.); (V.R.); (B.M.); (S.P.)
- Oncology Unit, Ospedale del Mare, 80147 Naples, Italy; (L.A.); (D.B.); (C.C.); (M.R.); (B.D.)
- CRCTR Coordinating Rare Tumors Reference Center of Campania Region, 80131 Naples, Italy; (M.T.); (G.P.)
- Correspondence:
| | - Emilio Francesco Giunta
- Department of Precision Medicine, Università Degli Studi della Campania Luigi Vanvitelli, 80131 Naples, Italy;
| | - Marianna Tortora
- CRCTR Coordinating Rare Tumors Reference Center of Campania Region, 80131 Naples, Italy; (M.T.); (G.P.)
| | - Marcello Curvietto
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, 80131 Naples, Italy; (M.C.); (M.G.V.); (E.S.)
| | - Laura Attademo
- Oncology Unit, Ospedale del Mare, 80147 Naples, Italy; (L.A.); (D.B.); (C.C.); (M.R.); (B.D.)
| | - Davide Bosso
- Oncology Unit, Ospedale del Mare, 80147 Naples, Italy; (L.A.); (D.B.); (C.C.); (M.R.); (B.D.)
| | - Cinzia Cardalesi
- Oncology Unit, Ospedale del Mare, 80147 Naples, Italy; (L.A.); (D.B.); (C.C.); (M.R.); (B.D.)
| | - Mario Rosanova
- Oncology Unit, Ospedale del Mare, 80147 Naples, Italy; (L.A.); (D.B.); (C.C.); (M.R.); (B.D.)
| | - Pietro De Placido
- Department of Clinical Medicine and Surgery, Università Degli Studi di Napoli “Federico II”, 80131 Naples, Italy; (P.D.P.); (E.P.); (V.R.); (B.M.); (S.P.)
| | - Erica Pietroluongo
- Department of Clinical Medicine and Surgery, Università Degli Studi di Napoli “Federico II”, 80131 Naples, Italy; (P.D.P.); (E.P.); (V.R.); (B.M.); (S.P.)
| | - Vittorio Riccio
- Department of Clinical Medicine and Surgery, Università Degli Studi di Napoli “Federico II”, 80131 Naples, Italy; (P.D.P.); (E.P.); (V.R.); (B.M.); (S.P.)
| | - Brigitta Mucci
- Department of Clinical Medicine and Surgery, Università Degli Studi di Napoli “Federico II”, 80131 Naples, Italy; (P.D.P.); (E.P.); (V.R.); (B.M.); (S.P.)
| | - Sara Parola
- Department of Clinical Medicine and Surgery, Università Degli Studi di Napoli “Federico II”, 80131 Naples, Italy; (P.D.P.); (E.P.); (V.R.); (B.M.); (S.P.)
| | - Maria Grazia Vitale
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, 80131 Naples, Italy; (M.C.); (M.G.V.); (E.S.)
| | - Giovannella Palmieri
- CRCTR Coordinating Rare Tumors Reference Center of Campania Region, 80131 Naples, Italy; (M.T.); (G.P.)
| | - Bruno Daniele
- Oncology Unit, Ospedale del Mare, 80147 Naples, Italy; (L.A.); (D.B.); (C.C.); (M.R.); (B.D.)
| | - Ester Simeone
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, 80131 Naples, Italy; (M.C.); (M.G.V.); (E.S.)
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Köhler J, Jänne PA. If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer. Int J Mol Sci 2021; 22:3025. [PMID: 33809660 PMCID: PMC8002337 DOI: 10.3390/ijms22063025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 12/26/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is "undruggable", (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically "cold" tumors into "hot" ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich's century-old "magic bullet" vision with Rudolf Virchow's cancer inflammation theory.
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Affiliation(s)
- Jens Köhler
- Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA 02215, USA
| | - Pasi A. Jänne
- Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Boston, MA 02215, USA
- Belfer Center for Applied Cancer Sciences, Boston, MA 02215, USA
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36
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Barbosa R, Acevedo LA, Marmorstein R. The MEK/ERK Network as a Therapeutic Target in Human Cancer. Mol Cancer Res 2021; 19:361-374. [PMID: 33139506 PMCID: PMC7925338 DOI: 10.1158/1541-7786.mcr-20-0687] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/01/2020] [Accepted: 10/27/2020] [Indexed: 11/16/2022]
Abstract
The RAS-RAF-MEK-ERK pathway is the most well-studied of the MAPK cascades and is critical for cell proliferation, differentiation, and survival. Abnormalities in regulation resulting from mutations in components of this pathway, particularly in upstream proteins, RAS and RAF, are responsible for a significant fraction of human cancers and nearly all cutaneous melanomas. Activation of receptor tyrosine kinases by growth factors and various extracellular signals leads to the sequential activation of RAS, RAF, MEK, and finally ERK, which activates numerous transcription factors and facilitates oncogenesis in the case of aberrant pathway activation. While extensive studies have worked to elucidate the activation mechanisms and structural components of upstream MAPK components, comparatively less attention has been directed toward the kinases, MEK and ERK, due to the infrequency of oncogenic-activating mutations in these kinases. However, acquired drug resistance has become a major issue in the treatment of RAS- and RAF-mutated cancers. Targeting the terminal kinases in the MAPK cascade has shown promise for overcoming many of these resistance mechanisms and improving treatment options for patients with MAPK-aberrant cancers. Here, we will describe the role of MEK and ERK in MAPK signaling and summarize the current understanding of their interaction and activation mechanisms. We will also discuss existing approaches for targeting MEK and ERK, and the benefits of alternative strategies. Areas requiring further exploration will be highlighted to guide future research endeavors and aid in the development of alternative therapeutic strategies to combat surmounting drug resistance in treating MAPK-mediated cancers. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/3/361/F1.large.jpg.
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Affiliation(s)
- Renee Barbosa
- School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lucila A Acevedo
- Department of Biochemistry & Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ronen Marmorstein
- Department of Biochemistry & Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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37
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The ERK mitogen-activated protein kinase signaling network: the final frontier in RAS signal transduction. Biochem Soc Trans 2021; 49:253-267. [PMID: 33544118 DOI: 10.1042/bst20200507] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/30/2020] [Accepted: 01/08/2021] [Indexed: 12/11/2022]
Abstract
The RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade is aberrantly activated in a diverse set of human cancers and the RASopathy group of genetic developmental disorders. This protein kinase cascade is one of the most intensely studied cellular signaling networks and has been frequently targeted by the pharmaceutical industry, with more than 30 inhibitors either approved or under clinical evaluation. The ERK-MAPK cascade was originally depicted as a serial and linear, unidirectional pathway that relays extracellular signals, such as mitogenic stimuli, through the cytoplasm to the nucleus. However, we now appreciate that this three-tiered protein kinase cascade is a central core of a complex network with dynamic signaling inputs and outputs and autoregulatory loops. Despite our considerable advances in understanding the ERK-MAPK network, the ability of cancer cells to adapt to the inhibition of key nodes reveals a level of complexity that remains to be fully understood. In this review, we summarize important developments in our understanding of the ERK-MAPK network and identify unresolved issues for ongoing and future study.
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Flemington V, Davies EJ, Robinson D, Sandin LC, Delpuech O, Zhang P, Hanson L, Farrington P, Bell S, Falenta K, Gibbons FD, Lindsay N, Smith A, Wilson J, Roberts K, Tonge M, Hopcroft P, Willis SE, Roudier MP, Rooney C, Coker EA, Jaaks P, Garnett MJ, Fawell SE, Jones CD, Ward RA, Simpson I, Cosulich SC, Pease JE, Smith PD. AZD0364 Is a Potent and Selective ERK1/2 Inhibitor That Enhances Antitumor Activity in KRAS-Mutant Tumor Models when Combined with the MEK Inhibitor, Selumetinib. Mol Cancer Ther 2020; 20:238-249. [PMID: 33273059 DOI: 10.1158/1535-7163.mct-20-0002] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 07/13/2020] [Accepted: 11/06/2020] [Indexed: 11/16/2022]
Abstract
The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF-mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS-mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signaling in KRAS-mutant tumors and achieve meaningful clinical benefit. Here, we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro, AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF-mutant and KRAS-mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose- and time-dependent modulation of ERK1/2-dependent signaling biomarkers resulting in tumor regression in sensitive BRAF- and KRAS-mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor, selumetinib (AZD6244 and ARRY142886), enhances efficacy in KRAS-mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signaling pathway that is not achievable with single-agent treatment. The AZD0364 and selumetinib combination also results in significant tumor regressions in multiple KRAS-mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS-mutant tumors.
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Affiliation(s)
- Vikki Flemington
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom.
| | - Emma J Davies
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - David Robinson
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Linda C Sandin
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Oona Delpuech
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Pei Zhang
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Lyndsey Hanson
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Paul Farrington
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Sigourney Bell
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Katarzyna Falenta
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Francis D Gibbons
- DMPK, Oncology, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom and Waltham, Massachusetts
| | - Nicola Lindsay
- DMPK, Oncology, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom and Waltham, Massachusetts
| | - Aaron Smith
- DMPK, Oncology, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom and Waltham, Massachusetts
| | - Joanne Wilson
- DMPK, Oncology, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom and Waltham, Massachusetts
| | - Karen Roberts
- Discovery Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Michael Tonge
- Discovery Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Philip Hopcroft
- Discovery Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Sophie E Willis
- Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Martine P Roudier
- Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | - Claire Rooney
- Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | | | - Patricia Jaaks
- Wellcome Sanger Institute, Cambridge, England, United Kingdom
| | | | | | | | - Richard A Ward
- Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
| | | | | | | | - Paul D Smith
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, England, United Kingdom
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Scheiblecker L, Kollmann K, Sexl V. CDK4/6 and MAPK-Crosstalk as Opportunity for Cancer Treatment. Pharmaceuticals (Basel) 2020; 13:E418. [PMID: 33255177 PMCID: PMC7760252 DOI: 10.3390/ph13120418] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 11/20/2020] [Accepted: 11/22/2020] [Indexed: 02/06/2023] Open
Abstract
Despite the development of targeted therapies and novel inhibitors, cancer remains an undefeated disease. Resistance mechanisms arise quickly and alternative treatment options are urgently required, which may be partially met by drug combinations. Protein kinases as signaling switchboards are frequently deregulated in cancer and signify vulnerable nodes and potential therapeutic targets. We here focus on the cell cycle kinase CDK6 and on the MAPK pathway and on their interplay. We also provide an overview on clinical studies examining the effects of combinational treatments currently explored for several cancer types.
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Affiliation(s)
| | | | - Veronika Sexl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; (L.S.); (K.K.)
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40
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Daemen A, Cooper JE, Myrta S, Wongchenko MJ, Lin E, Long JE, Foreman O, Modrusan Z, Tremayne JR, de la Cruz CC, Merchant M, Martin SE, Yan Y, Junttila MR. Transcriptional Subtypes Resolve Tumor Heterogeneity and Identify Vulnerabilities to MEK Inhibition in Lung Adenocarcinoma. Clin Cancer Res 2020; 27:1162-1173. [PMID: 33023953 DOI: 10.1158/1078-0432.ccr-20-1835] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/22/2020] [Accepted: 09/30/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Lung adenocarcinomas comprise the largest fraction of non-small cell lung cancer, which is the leading cause of cancer-related deaths. Seventy-five percent of adenocarcinomas lack targeted therapies because of scarcity of druggable drivers. Here, we classified tumors on the basis of signaling similarities and discovered subgroups within this unmet patient population. EXPERIMENTAL DESIGN We leveraged transcriptional data from >800 early- and advanced-stage patients. RESULTS We identified three robust subtypes dubbed mucinous, proliferative, and mesenchymal with respective pathway phenotypes. These transcriptional states lack discrete and causative mutational etiology as evidenced by similarly distributed oncogenic drivers, including KRAS and EGFR. The subtypes capture heterogeneity even among tumors lacking known oncogenic drivers. Paired multi-regional intratumoral biopsies demonstrated unified subtypes despite divergently evolved prooncogenic mutations, indicating subtype stability during selective pressure. Heterogeneity among in vitro and in vivo preclinical models is expounded by the human lung adenocarcinoma subtypes and can be leveraged to discover subtype-specific vulnerabilities. As proof of concept, we identified differential subtype response to MEK pathway inhibition in a chemical library screen of 89 lung cancer cell lines, which reproduces across model systems and a clinical trial. CONCLUSIONS Our findings support forward translational relevance of transcriptional subtypes, where further exploration therein may improve lung adenocarcinoma treatment.See related commentary by Skoulidis, p. 913.
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Affiliation(s)
- Anneleen Daemen
- Department of Bioinformatics & Computational Biology, Genentech, Inc., South San Francisco, California.
| | - Jonathan E Cooper
- Department of Molecular Oncology, Genentech, Inc., South San Francisco, California
| | - Szymon Myrta
- Roche Global IT Solution Centre, Roche, Warsaw, Poland
| | - Matthew J Wongchenko
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California
| | - Eva Lin
- Department of Molecular Oncology, Genentech, Inc., South San Francisco, California
| | - Jason E Long
- Department of Molecular Oncology, Genentech, Inc., South San Francisco, California
| | - Oded Foreman
- Department of Research Pathology, Genentech, Inc., South San Francisco, California
| | - Zora Modrusan
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, California
| | - Jarrod R Tremayne
- Department of Translational Oncology, Genentech, Inc., South San Francisco, California
| | - Cecile C de la Cruz
- Department of Translational Oncology, Genentech, Inc., South San Francisco, California
| | - Mark Merchant
- Department of Translational Oncology, Genentech, Inc., South San Francisco, California
| | - Scott E Martin
- Department of Molecular Oncology, Genentech, Inc., South San Francisco, California
| | - Yibing Yan
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California
| | - Melissa R Junttila
- Department of Molecular Oncology, Genentech, Inc., South San Francisco, California.
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Targeted therapies in melanoma beyond BRAF: targeting NRAS-mutated and KIT-mutated melanoma. Curr Opin Oncol 2020; 32:79-84. [PMID: 31833955 DOI: 10.1097/cco.0000000000000606] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
PURPOSE OF REVIEW Melanoma treatment have been revolutionized since 2010 by the development of immune checkpoint inhibitors, and, for BRAF-mutated melanoma, targeted therapies based on BRAF and MEK inhibitors, which is a model of effective targeted therapy in cancer. However, patients with BRAF wild type cannot benefit for such treatments. In this review, we will focus on the current clinical development of targeted therapies beyond BRAF, in NRAS-mutated and KIT-altered melanoma. RECENT FINDINGS In NRAS-mutated melanoma, targeted therapies based on MEK inhibition are being developed as monotherapy or in combination with MAPK, PI3K or CDK4/6 inhibitor. Targeted therapies of KIT-altered melanoma patients is based in KIT inhibitor (mostly imatinib, nilotinib), although for both melanoma subtypes, results are for now disappointing as compared with BRAF and MEK inhibitors in BRAF-mutated melanoma. SUMMARY Combined therapeutic targeted strategies are awaited in NRAS-mutated and KIT-altered melanoma and could provide additional benefit.
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Integrated phosphoproteomics and transcriptional classifiers reveal hidden RAS signaling dynamics in multiple myeloma. Blood Adv 2020; 3:3214-3227. [PMID: 31698452 DOI: 10.1182/bloodadvances.2019000303] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 08/23/2019] [Indexed: 02/06/2023] Open
Abstract
A major driver of multiple myeloma (MM) is thought to be aberrant signaling, yet no kinase inhibitors have proven successful in the clinic. Here, we employed an integrated, systems approach combining phosphoproteomic and transcriptome analysis to dissect cellular signaling in MM to inform precision medicine strategies. Unbiased phosphoproteomics initially revealed differential activation of kinases across MM cell lines and that sensitivity to mammalian target of rapamycin (mTOR) inhibition may be particularly dependent on mTOR kinase baseline activity. We further noted differential activity of immediate downstream effectors of Ras as a function of cell line genotype. We extended these observations to patient transcriptome data in the Multiple Myeloma Research Foundation CoMMpass study. A machine-learning-based classifier identified surprisingly divergent transcriptional outputs between NRAS- and KRAS-mutated tumors. Genetic dependency and gene expression analysis revealed mutated Ras as a selective vulnerability, but not other MAPK pathway genes. Transcriptional analysis further suggested that aberrant MAPK pathway activation is only present in a fraction of RAS-mutated vs wild-type RAS patients. These high-MAPK patients, enriched for NRAS Q61 mutations, have inferior outcomes, whereas RAS mutations overall carry no survival impact. We further developed an interactive software tool to relate pharmacologic and genetic kinase dependencies in myeloma. Collectively, these predictive models identify vulnerable signaling signatures and highlight surprising differences in functional signaling patterns between NRAS and KRAS mutants invisible to the genomic landscape. These results will lead to improved stratification of MM patients in precision medicine trials while also revealing unexplored modes of Ras biology in MM.
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Fish JE, Flores Suarez CP, Boudreau E, Herman AM, Gutierrez MC, Gustafson D, DiStefano PV, Cui M, Chen Z, De Ruiz KB, Schexnayder TS, Ward CS, Radovanovic I, Wythe JD. Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling. Circ Res 2020; 127:727-743. [PMID: 32552404 PMCID: PMC7447191 DOI: 10.1161/circresaha.119.316500] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Supplemental Digital Content is available in the text. Rationale: We previously identified somatic activating mutations in the KRAS (Kirsten rat sarcoma viral oncogene homologue) gene in the endothelium of the majority of human sporadic brain arteriovenous malformations; a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to arteriovenous malformations, remains unknown. Objective: To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for arteriovenous malformations. Methods and Results: Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce brain arteriovenous malformations. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity but instead seem to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent arteriovenous malformations in zebrafish are refractory to inhibition of the downstream effector PI3K but instead require active MEK (mitogen-activated protein kinase kinase 1) signaling. Conclusions: We demonstrate that active KRAS expression in the endothelium is sufficient for brain arteriovenous malformations, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for arteriovenous malformation patients.
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Affiliation(s)
- Jason E Fish
- From the Toronto General Hospital Research Institute (J.E.F., E.B., D.G., P.V.D., Z.C.), University Health Network, Canada.,Peter Munk Cardiac Centre (J.E.F.), University Health Network, Canada.,Department of Laboratory Medicine and Pathobiology (J.E.F., D.G.), University of Toronto, Canada
| | - Carlos Perfecto Flores Suarez
- Cardiovascular Research Institute (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., J.D.W.), Baylor College of Medicine, Houston, TX.,Department of Molecular Physiology and Biophysics (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., T.S.S., C.S.W., J.D.W.), Baylor College of Medicine, Houston, TX
| | - Emilie Boudreau
- From the Toronto General Hospital Research Institute (J.E.F., E.B., D.G., P.V.D., Z.C.), University Health Network, Canada
| | - Alexander M Herman
- Cardiovascular Research Institute (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., J.D.W.), Baylor College of Medicine, Houston, TX.,Department of Molecular Physiology and Biophysics (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., T.S.S., C.S.W., J.D.W.), Baylor College of Medicine, Houston, TX
| | - Manuel Cantu Gutierrez
- Cardiovascular Research Institute (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., J.D.W.), Baylor College of Medicine, Houston, TX.,Department of Molecular Physiology and Biophysics (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., T.S.S., C.S.W., J.D.W.), Baylor College of Medicine, Houston, TX.,Graduate Program in Developmental Biology (M.C.G., J.D.W.), Baylor College of Medicine, Houston, TX
| | - Dakota Gustafson
- From the Toronto General Hospital Research Institute (J.E.F., E.B., D.G., P.V.D., Z.C.), University Health Network, Canada.,Department of Laboratory Medicine and Pathobiology (J.E.F., D.G.), University of Toronto, Canada
| | - Peter V DiStefano
- From the Toronto General Hospital Research Institute (J.E.F., E.B., D.G., P.V.D., Z.C.), University Health Network, Canada
| | - Meng Cui
- Cardiovascular Research Institute (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., J.D.W.), Baylor College of Medicine, Houston, TX.,Department of Molecular Physiology and Biophysics (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., T.S.S., C.S.W., J.D.W.), Baylor College of Medicine, Houston, TX
| | - Zhiqi Chen
- From the Toronto General Hospital Research Institute (J.E.F., E.B., D.G., P.V.D., Z.C.), University Health Network, Canada
| | - Karen Berman De Ruiz
- Cardiovascular Research Institute (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., J.D.W.), Baylor College of Medicine, Houston, TX.,Department of Molecular Physiology and Biophysics (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., T.S.S., C.S.W., J.D.W.), Baylor College of Medicine, Houston, TX
| | - Taylor S Schexnayder
- Department of Molecular Physiology and Biophysics (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., T.S.S., C.S.W., J.D.W.), Baylor College of Medicine, Houston, TX.,and Advanced Technology Cores (T.S.S., C.S.W.), Baylor College of Medicine, Houston, TX
| | - Christopher S Ward
- Department of Molecular Physiology and Biophysics (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., T.S.S., C.S.W., J.D.W.), Baylor College of Medicine, Houston, TX.,and Advanced Technology Cores (T.S.S., C.S.W.), Baylor College of Medicine, Houston, TX
| | - Ivan Radovanovic
- Krembil Research Institute (I.R.), University Health Network, Canada.,Division of Neurosurgery, Sprott Department of Surgery (I.R.), University Health Network, Canada.,Department of Surgery (I.R.), University of Toronto, Canada
| | - Joshua D Wythe
- Cardiovascular Research Institute (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., J.D.W.), Baylor College of Medicine, Houston, TX.,Department of Molecular Physiology and Biophysics (C.P.F.S., A.M.H., M.C.G., M.C., K.B.D.R., T.S.S., C.S.W., J.D.W.), Baylor College of Medicine, Houston, TX.,Graduate Program in Developmental Biology (M.C.G., J.D.W.), Baylor College of Medicine, Houston, TX
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Ozkan-Dagliyan I, Diehl JN, George SD, Schaefer A, Papke B, Klotz-Noack K, Waters AM, Goodwin CM, Gautam P, Pierobon M, Peng S, Gilbert TSK, Lin KH, Dagliyan O, Wennerberg K, Petricoin EF, Tran NL, Bhagwat SV, Tiu RV, Peng SB, Herring LE, Graves LM, Sers C, Wood KC, Cox AD, Der CJ. Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers. Cell Rep 2020; 31:107764. [PMID: 32553168 PMCID: PMC7393480 DOI: 10.1016/j.celrep.2020.107764] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 04/15/2020] [Accepted: 05/21/2020] [Indexed: 12/13/2022] Open
Abstract
We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.
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Affiliation(s)
- Irem Ozkan-Dagliyan
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - J Nathaniel Diehl
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Samuel D George
- Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Antje Schaefer
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Bjoern Papke
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Kathleen Klotz-Noack
- Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany
| | - Andrew M Waters
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Craig M Goodwin
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Prson Gautam
- Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland
| | - Mariaelena Pierobon
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Sen Peng
- Departments of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
| | - Thomas S K Gilbert
- UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Kevin H Lin
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
| | - Onur Dagliyan
- Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
| | - Krister Wennerberg
- Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland
| | - Emanuel F Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Nhan L Tran
- Departments of Cancer Biology and Neurosurgery, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA
| | | | - Ramon V Tiu
- Eli Lilly and Company, Indianapolis, IN 46285, USA
| | | | - Laura E Herring
- UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lee M Graves
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Christine Sers
- Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Berlin Institute of Health (BIH), Anna-Louise-Karsch-Str. 2, 10178 Berlin, Germany
| | - Kris C Wood
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
| | - Adrienne D Cox
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Channing J Der
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, 10117 Berlin, Germany.
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Abstract
RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. Even 10 years ago, RAS inhibitors were so elusive that RAS was termed 'undruggable'. Now, with the success of allele-specific covalent inhibitors against the most frequently mutated version of RAS in non-small-cell lung cancer, KRASG12C, we have the opportunity to evaluate the best therapeutic strategies to treat RAS-driven cancers. Mutation-specific biochemical properties, as well as the tissue of origin, are likely to affect the effectiveness of such treatments. Currently, direct inhibition of mutant RAS through allele-specific inhibitors provides the best therapeutic approach. Therapies that target RAS-activating pathways or RAS effector pathways could be combined with these direct RAS inhibitors, immune checkpoint inhibitors or T cell-targeting approaches to treat RAS-mutant tumours. Here we review recent advances in therapies that target mutant RAS proteins and discuss the future challenges of these therapies, including combination strategies.
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Weekes C, Lockhart A, LoRusso P, Murray E, Park E, Tagen M, Singh J, Sarkar I, Mueller L, Dokainish H, Shapiro G, Burris H. A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors. Oncologist 2020; 25:833-e1438. [PMID: 32311798 DOI: 10.1634/theoncologist.2020-0292] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 04/04/2020] [Indexed: 12/12/2022] Open
Abstract
LESSONS LEARNED Despite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug-drug interaction. Cycle 1 metabolic responses were observed by 18F-fluorodeoxyglucose-positron emission tomography but were not predictive of outcome measured by RECIST 1.1. BACKGROUND Simultaneous targeting of multiple nodes in the mitogen-activated protein kinase (MAPK) pathway offers the prospect of enhanced activity in RAS-RAF-mutant tumors. This phase Ib trial evaluated the combination of cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) in patients with locally advanced or metastatic solid tumors. METHODS Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Arm A consisted of concurrent cobimetinib and GDC-0994 once daily for 21 days of a 28-day cycle; Arm B consisted of intermittent dosing of cobimetinib on a 28-day cycle concurrent with GDC-0994 daily for 21 days of a 28-day cycle. RESULTS In total, 24 patients were enrolled. For Arm A, owing to cumulative grade 1-2 toxicity, the dose of cobimetinib was decreased. For Arm B, dose increases of GDC-0994 and cobimetinib were intolerable with grade 3 dose-limiting toxicities of myocardial infarction and rash. Pharmacokinetic data did not show evidence of a drug-drug interaction. Overall, seven patients had a best overall response of stable disease (SD) and one patient with pancreatic adenocarcinoma had an unconfirmed partial response. CONCLUSION The safety profile of MEK and ERK inhibition demonstrated classic MAPK inhibitor-related adverse events (AEs). However, overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination.
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Affiliation(s)
- Colin Weekes
- Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Albert Lockhart
- Division of Oncology, Washington University Medical School, St. Louis, Missouri, USA
| | - Patricia LoRusso
- Smilow Cancer Center, Yale University, New Haven, Connecticut, USA
| | - Elaine Murray
- Genentech, Inc., South San Francisco, California, USA
| | - Erica Park
- Genentech, Inc., South San Francisco, California, USA
| | - Mike Tagen
- Genentech, Inc., South San Francisco, California, USA
| | | | | | - Lars Mueller
- Genentech, Inc., South San Francisco, California, USA
| | | | | | - Howard Burris
- Sarah Cannon Research Institute, Nashville, Tennessee, USA
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Usta D, Sigaud R, Buhl JL, Selt F, Marquardt V, Pauck D, Jansen J, Pusch S, Ecker J, Hielscher T, Vollmer J, Sommerkamp AC, Rubner T, Hargrave D, van Tilburg CM, Pfister SM, Jones DTW, Remke M, Brummer T, Witt O, Milde T. A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF-Driven Pediatric Low-Grade Glioma Cells. Mol Cancer Ther 2020; 19:1736-1750. [PMID: 32451331 DOI: 10.1158/1535-7163.mct-19-1021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 04/11/2020] [Accepted: 05/15/2020] [Indexed: 11/16/2022]
Abstract
Pilocytic astrocytomas as well as other pediatric low-grade gliomas (pLGG) exhibit genetic events leading to aberrant activation of the MAPK pathway. The most common alterations are KIAA1549:BRAF fusions and BRAFV600E and NF1 mutations. Novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for the treatment of these single-pathway diseases. We aimed to develop an assay suitable for preclinical testing of MAPKi in pLGGs with the goal to identify novel MAPK pathway-suppressing synergistic drug combinations. A reporter plasmid (pDIPZ) with a MAPK-responsive ELK-1-binding element driving the expression of destabilized firefly luciferase was generated and packaged using a lentiviral vector system. Pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAFV600E mutation (BT-40) background, respectively, were stably transfected. Modulation of the MAPK pathway activity by MAPKi was measured using the luciferase reporter and validated by detection of phosphorylated protein levels. A screening of a MAPKi library was performed, and synergy of selected combinations was calculated. Screening of a MAPKi library revealed MEK inhibitors as the class inhibiting the pathway with the lowest IC50s, followed by ERK and next-generation RAF inhibitors. Combination treatments with different MAPKi classes showed synergistic effects in BRAF fusion as well as BRAFV600E mutation backgrounds. Here, we report a novel reporter assay for medium- to high-throughput preclinical drug testing in pLGG cell lines. The assay confirmed MEK, ERK, and next-generation RAF inhibitors as potential treatment approaches for KIAA1549:BRAF and BRAFV600E-mutated pLGGs. In addition, the assay revealed that combination treatments synergistically suppressed MAPK pathway activity.
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Affiliation(s)
- Diren Usta
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Romain Sigaud
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Juliane L Buhl
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Florian Selt
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Viktoria Marquardt
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Germany, and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - David Pauck
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Germany, and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jennifer Jansen
- Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany, Centre for Biological Signalling Studies BIOSS, University of Freiburg, Comprehensive Cancer Center Freiburg (CCCF) and German Consortium for Translational Cancer Research (DKTK), Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stefan Pusch
- Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.,Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Jonas Ecker
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Hielscher
- Division of Biostatistics, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Johanna Vollmer
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Alexander C Sommerkamp
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.,Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tobias Rubner
- Flow Cytometry Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Darren Hargrave
- Neurooncology and Experimental Therapeutics, Great Ormond Street Hospital for Children, London, United Kingdom
| | - Cornelis M van Tilburg
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan M Pfister
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.,Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - David T W Jones
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marc Remke
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Germany, and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tilman Brummer
- Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany, Centre for Biological Signalling Studies BIOSS, University of Freiburg, Comprehensive Cancer Center Freiburg (CCCF) and German Consortium for Translational Cancer Research (DKTK), Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Olaf Witt
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Till Milde
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. .,Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.,KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
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Chin HM, Lai DK, Falchook GS. Extracellular Signal-Regulated Kinase (ERK) Inhibitors in Oncology Clinical Trials. ACTA ACUST UNITED AC 2020. [DOI: 10.4103/jipo.jipo_17_18] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Abstract
The mitogen-activated protein kinase (MAPK) pathway consists of the series of protein kinases RAS-RAF-MEK-Extracellular signal-regulated kinase (ERK), and its function is important to cell proliferation, differentiation, motility, and survival. Certain mutations in the pathway, such as KRAS or BRAF V600 mutations are associated with cancer. Inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic, but a variety of selective ERK inhibitors are still being tested in clinical studies. To date, common adverse events associated with ERK inhibitors include diarrhea, nausea, fatigue, and rash. ERK inhibitors have demonstrated preliminary antitumor activity and may be most effective against cancers with RAS, RAF, or MAPK pathway alterations. This review discusses the MAPK pathway, the biological rationale for ERK inhibitors, and clinical trials involving ERK inhibitors.
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Affiliation(s)
| | - David K Lai
- Rice University, Denver, CO, USA
- University of Colorado – Denver, CO, USA
| | - Gerald S Falchook
- Rice University, Denver, CO, USA
- Sarah Cannon Research Institute at HealthONE, Denver, CO, USA
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Abstract
PURPOSE OF REVIEW The current review aims to highlight the frequency of RAS mutations in pediatric leukemias and solid tumors and to propose strategies for targeting oncogenic RAS in pediatric cancers. RECENT FINDINGS The three RAS genes (HRAS, NRAS, and KRAS) comprise the most frequently mutated oncogene family in human cancer. RAS mutations are commonly observed in three of the leading causes of cancer death in the United States, namely lung cancer, pancreatic cancer, and colorectal cancer. The association of RAS mutations with these aggressive malignancies inspired the creation of the National Cancer Institute RAS initiative and spurred intense efforts to develop strategies to inhibit oncogenic RAS, with much recent success. RAS mutations are frequently observed in pediatric cancers; however, recent advances in anti-RAS drug development have yet to translate into pediatric clinical trials. SUMMARY We find that RAS is mutated in common and rare pediatric malignancies and that oncogenic RAS confers a functional dependency in these cancers. Many strategies for targeting RAS are being pursued for malignancies that primarily affect adults and there is a clear need for inclusion of pediatric patients in clinical trials of these agents.
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ERK Inhibitor LY3214996 Targets ERK Pathway–Driven Cancers: A Therapeutic Approach Toward Precision Medicine. Mol Cancer Ther 2019; 19:325-336. [DOI: 10.1158/1535-7163.mct-19-0183] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 09/10/2019] [Accepted: 11/12/2019] [Indexed: 11/16/2022]
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