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Miglio U, Berrino E, Avanzato D, Molineris I, Miano V, Milan M, Lanzetti L, Morelli E, Hughes JM, De Bortoli M, Sapino A, Venesio T. Inhibition of the LINE1-derived MET transcript induces apoptosis and oncoprotein knockdown in cancer cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102529. [PMID: 40291377 PMCID: PMC12032326 DOI: 10.1016/j.omtn.2025.102529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 03/27/2025] [Indexed: 04/30/2025]
Abstract
The expression of intragenic long interspersed nuclear elements 1 (LINE1s) can generate chimeric sequences disrupting host gene transcription. Among these, L1-MET, within mesenchymal epithelial transition (MET) oncogene, is particularly interesting, as its expression has been associated with the acquisition of tumorigenic phenotypes and cancer progression. We investigated the effects of targeting L1-MET in eight cancer cell lines derived from breast, lung, and gastrointestinal cancers, as well as in non-transformed human fibroblasts and lymphocytes, using specifically developed modified antisense oligonucleotides. Inhibition of L1-MET resulted in decreased cell viability, increased apoptosis, and gene expression profile reprogramming in cancer cells, including significant downregulation of MET and epidermal growth factor receptor (EGFR) proteins. These effects were related to the L1-MET/MET expression levels and the type of cellular addiction, with pronounced impacts in cells harboring MET gene amplification and EGFR-activating mutations. They were also detectable, though less pronounced, in cancer cells with steady-state levels of MET and EGFR proteins or addiction to other oncogenes. We demonstrate that targeting L1-MET can knockdown MET and EGFR protein. The restricted expression of L1-MET to cancer cells suggests that its inhibition could be an effective strategy to induce death in oncogene-addicted tumor cells and offers a potential means to overcome the limitations of conventional targeted therapies.
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Affiliation(s)
- Umberto Miglio
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy
| | - Enrico Berrino
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Daniele Avanzato
- Department of Oncology, University of Torino Medical School, 10043 Orbassano, TO, Italy
| | - Ivan Molineris
- Department of Life Sciences and System Biology and MBC, University of Torino, 10123 Torino, Italy
| | - Valentina Miano
- Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, TO, Italy
| | - Melissa Milan
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy
| | - Letizia Lanzetti
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy
- Department of Oncology, University of Torino Medical School, 10043 Orbassano, TO, Italy
| | - Eugenio Morelli
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy
- Department of Oncology, University of Torino Medical School, 10043 Orbassano, TO, Italy
| | - James M. Hughes
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy
| | - Michele De Bortoli
- Department of Clinical and Biological Sciences, University of Torino, 10043 Orbassano, TO, Italy
| | - Anna Sapino
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy
- Department of Medical Sciences, University of Torino, 10126 Torino, Italy
| | - Tiziana Venesio
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Candiolo, TO, Italy
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Waissengrin B, Reckamp KL. An evaluation of patritumab deruxtecan for the treatment of EGFR-mutated non-small cell lung cancer. Expert Opin Biol Ther 2025:1-9. [PMID: 40374579 DOI: 10.1080/14712598.2025.2507833] [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: 02/17/2025] [Revised: 04/28/2025] [Accepted: 05/14/2025] [Indexed: 05/17/2025]
Abstract
INTRODUCTION Epidermal growth factor receptor (EGFR) mutations represent targetable alterations in non-small cell lung cancer (NSCLC). The treatment landscape in the frontline setting for patients with advanced EGFR-mutated NSCLC is evolving with increasing treatment options. EGFR tyrosine kinase inhibitors (TKIs) have significantly improved outcomes, but resistance inevitably develops, necessitating alternative strategies. AREAS COVERED Patritumab deruxtecan is a novel antibody-drug conjugate targeted human epidermal growth factor receptor-3 (HER3), delivering a topoisomerase-I inhibitor payload to HER3-expressing cancer cells. Phase I and II studies have demonstrated efficacy in patients with EGFR-mutant NSCLC with disease progression after prior therapies, including third-generation EGFR TKIs and platinum-based chemotherapy. The phase-II trial reported an objective response rate of 39% and a median progression-free survival of 5.5 months. Patritumab deruxtecan is associated with notable toxicities, including grade 3 and higher hematologic adverse events, gastrointestinal toxicity, and interstitial lung disease (ILD). ILD occurred in 5.3% of patients in the Phase-II study. Early detection and management are crucial for minimizing the risk of complications. EXPERT OPINION Patients with advanced EGFR-mutant NSCLC who have received TKI therapy and chemotherapy have limited treatment options. Patritumab deruxtecan demonstrates clinical activity in this population with manageable side effects, addressing an unmet need for patients.
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Affiliation(s)
- Barliz Waissengrin
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Karen L Reckamp
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Starble RM, Sun EG, Gbyli R, Radda J, Lu J, Jensen TB, Sun N, Khudaverdyan N, Hu B, Melnick MA, Zhao S, Roper N, Wang GG, Song J, Politi K, Wang S, Xiao AZ. Epigenetic priming promotes acquisition of tyrosine kinase inhibitor resistance and oncogene amplification in human lung cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.26.634826. [PMID: 39974875 PMCID: PMC11838195 DOI: 10.1101/2025.01.26.634826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
In mammalian cells, gene copy number is tightly controlled to maintain gene expression and genome stability. However, a common molecular feature across cancer types is oncogene amplification, which promotes cancer progression by drastically increasing the copy number and expression of tumor-promoting genes. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification occurs in over 40% of patients' tumors. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the mechanisms facilitating oncogene amplification are not fully understood. Here, we find that LUADs exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naïve tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. We identified a global chromatin priming effect during the acquisition of TKI resistance, marked by a dynamic increase of H3K27Ac, cohesin loading, and inter-TAD interactions, which occurs before the onset of oncogene amplification. Furthermore, we have found that the METTL7A protein, which was previously reported to localize to the endoplasmic reticulum and inner nuclear membrane, has a novel chromatin regulatory function by binding to amplified loci and regulating cohesin recruitment and inter-TAD interactions. Surprisingly, we discovered that METTL7A remodels the chromatin landscape prior to large-scale copy number gains. Furthermore, while METTL7A depletion has little effect on the chromatin structure and proliferation of drug-naïve cells, METTL7A depletion prevents the formation and maintenance of TKI resistant-clones, highlighting the specific role of METTL7A as cells are becoming resistant. In summary, we discovered an unexpected mechanism required for the acquisition of TKI resistance regulated by a largely uncharacterized factor, METTL7A. This discovery sheds light into the maintenance of oncogene copy number and paves the way to the development of new therapeutics for preventing TKI resistance in LUAD.
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Affiliation(s)
- Rebecca M Starble
- Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
- Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Eric G Sun
- Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
- Present address: Tri-Institutional MD-PhD Program, Weill Cornell Medicine, Rockefeller University, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Rana Gbyli
- Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Jonathan Radda
- Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
| | - Jiuwei Lu
- Department of Biochemistry, University of California, Riverside, CA 92521, USA
| | - Tyler B Jensen
- Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Ning Sun
- Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
- Present address: Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China
| | - Nelli Khudaverdyan
- Department of Biochemistry, University of California, Riverside, CA 92521, USA
| | - Bomiao Hu
- Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA
| | | | - Shuai Zhao
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Nitin Roper
- Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
| | - Gang Greg Wang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Jikui Song
- Department of Biochemistry, University of California, Riverside, CA 92521, USA
| | - Katerina Politi
- Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA
- Yale Cancer Center, New Haven, CT 06520, USA
- Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, CT 06510, USA
| | - Siyuan Wang
- Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
- Department of Cell Biology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Andrew Z Xiao
- Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA
- Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
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Ou X, Gao G, Habaz IA, Wang Y. Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies. MedComm (Beijing) 2024; 5:e694. [PMID: 39184861 PMCID: PMC11344283 DOI: 10.1002/mco2.694] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 07/24/2024] [Accepted: 07/28/2024] [Indexed: 08/27/2024] Open
Abstract
Tyrosine kinase inhibitor (TKI)-targeted therapy has revolutionized cancer treatment by selectively blocking specific signaling pathways crucial for tumor growth, offering improved outcomes with fewer side effects compared with conventional chemotherapy. However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistance, including on-target mechanisms and off-target mechanisms, as well as changes in the tumor histology and tumor microenvironment (intrinsic mechanisms). Additionally, we summarized current therapeutic approaches aiming at circumventing TKI resistance, including the development of next-generation TKIs and combination therapies. We also discussed emerging strategies such as the use of dual-targeted antibodies and PROteolysis Targeting Chimeras. Furthermore, we explored future directions in TKI-targeted therapy, including the methods for detecting and monitoring drug resistance during treatment, identification of novel targets, exploration of dual-acting kinase inhibitors, application of nanotechnologies in targeted therapy, and so on. Overall, this review provides a comprehensive overview of the challenges and opportunities in TKI-targeted therapy, aiming to advance our understanding of resistance mechanisms and guide the development of more effective therapeutic approaches in cancer treatment.
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Affiliation(s)
- Xuejin Ou
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
| | - Ge Gao
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
- Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China HospitalSichuan UniversityChengduChina
| | - Inbar A. Habaz
- Department of Biochemistry and Biomedical SciencesMcMaster UniversityHamiltonOntarioCanada
| | - Yongsheng Wang
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China HospitalSichuan UniversityChengduChina
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Fukuda S, Suda K, Hamada A, Oiki H, Ohara S, Ito M, Soh J, Mitsudomi T, Tsutani Y. Potential Utility of a 4th-Generation EGFR-TKI and Exploration of Resistance Mechanisms-An In Vitro Study. Biomedicines 2024; 12:1412. [PMID: 39061985 PMCID: PMC11273927 DOI: 10.3390/biomedicines12071412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/17/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024] Open
Abstract
The emergence of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd-generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after front-line osimertinib treatment failure because of a secondary mutation. We also established acquired resistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however, it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020-resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial-to-mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome secondary mutations after front-line osimertinib. We found that off-target mechanisms that cause resistance to earlier-generation TKIs will also cause resistance to 4G TKIs.
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Affiliation(s)
| | - Kenichi Suda
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan; (S.F.); (A.H.); (H.O.); (S.O.); (M.I.); (J.S.); (T.M.); (Y.T.)
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Wallenta Law J, Bapat B, Sweetnam C, Mohammed H, McBratney A, Izano MA, Scannell Bryan M, Spencer S, Schroeder B, Hostin D, Simon GR, Berry AB. Real-World Impact of Comprehensive Genomic Profiling on Biomarker Detection, Receipt of Therapy, and Clinical Outcomes in Advanced Non-Small Cell Lung Cancer. JCO Precis Oncol 2024; 8:e2400075. [PMID: 38754057 PMCID: PMC11371096 DOI: 10.1200/po.24.00075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/13/2024] [Accepted: 03/29/2024] [Indexed: 05/18/2024] Open
Abstract
PURPOSE Therapeutic decision making for patients with advanced non-small cell lung cancer (aNSCLC) includes a growing number of options for genomic, biomarker-guided, targeted therapies. We compared actionable biomarker detection, targeted therapy receipt, and real-world overall survival (rwOS) in patients with aNSCLC tested with comprehensive genomic profiling (CGP) versus small panel testing (SP) in real-world community health systems. METHODS Patients older than 18 years diagnosed with aNSCLC between January 1, 2015, and December 31, 2020, who received biomarker testing were followed until death or study end (September 30, 2021), and categorized by most comprehensive testing during follow-up: SP (≤52 genes) or CGP (>52 genes). RESULTS Among 3,884 patients (median age, 68 years; 50% female; 73% non-Hispanic White), 20% received CGP and 80% SP. The proportion of patients with ≥one actionable biomarker (actionability) was significantly higher in CGP than in SP (32% v 14%; P < .001). Of patients with actionability, 43% (CGP) and 38% (SP) received matched therapies (P = .20). Among treated patients, CGP before first-line treatment was associated with higher likelihood of matched therapy in any line (odds ratio, 3.2 [95% CI, 1.84 to 5.53]). CGP testing (hazard ratio [HR], 0.80 [95% CI, 0.72 to 0.89]) and actionability (HR, 0.84 [95% CI, 0.77 to 0.91]) were associated with reduced risk of mortality. Among treated patients with actionability, matched therapy receipt showed improved median rwOS in months in CGP (34 [95% CI, 21 to 49] matched v 14 [95% CI, 10 to 18] unmatched) and SP (27 [95% CI, 21 to 43] matched v 10 [95% CI, 8 to 14] unmatched). CONCLUSION Patients who received CGP had improved detection of actionable biomarkers and greater use of matched therapies, both of which were associated with significant increases in survival.
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Kumar V, Yochum ZA, Devadassan P, Huang EHB, Miller E, Baruwal R, Rumde PH, GaitherDavis AL, Stabile LP, Burns TF. TWIST1 is a critical downstream target of the HGF/MET pathway and is required for MET driven acquired resistance in oncogene driven lung cancer. Oncogene 2024; 43:1431-1444. [PMID: 38485737 PMCID: PMC11068584 DOI: 10.1038/s41388-024-02987-5] [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: 11/21/2023] [Revised: 02/15/2024] [Accepted: 02/19/2024] [Indexed: 03/19/2024]
Abstract
MET amplification/mutations are important targetable oncogenic drivers in NSCLC, however, acquired resistance is inevitable and the majority of patients with targetable MET alterations fail to respond to MET tyrosine kinase inhibitors (TKIs). Furthermore, MET amplification is among the most common mediators of TKI resistance. As such, novel therapies to target MET pathway and overcome MET TKI resistance are clearly needed. Here we show that the epithelial-mesenchymal transition (EMT) transcription factor, TWIST1 is a key downstream mediator of HGF/MET induced resistance through suppression of p27 and targeting TWIST1 can overcome resistance. We found that TWIST1 is overexpressed at the time of TKI resistance in multiple MET-dependent TKI acquired resistance PDX models. We have shown for the first time that MET directly stabilized the TWIST protein leading to TKI resistance and that TWIST1 was required for MET-driven lung tumorigenesis as well as could induce MET TKI resistance when overexpressed. TWIST1 mediated MET TKI resistance through suppression of p27 expression and genetic or pharmacologic inhibition of TWIST1 overcame TKI resistance in vitro and in vivo. Our findings suggest that targeting TWIST1 may be an effective therapeutic strategy to overcome resistance in MET-driven NSCLC as well as in other oncogene driven subtypes in which MET amplification is the resistance mechanism.
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Affiliation(s)
- Vinod Kumar
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Zachary A Yochum
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Medicine, Medical Oncology, Yale School of Medicine, New Haven, CT, USA
| | - Princey Devadassan
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Eric H-B Huang
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Ethan Miller
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Roja Baruwal
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Purva H Rumde
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Autumn L GaitherDavis
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Laura P Stabile
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Timothy F Burns
- Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Belloni A, Pugnaloni A, Rippo MR, Di Valerio S, Giordani C, Procopio AD, Bronte G. The cell line models to study tyrosine kinase inhibitors in non-small cell lung cancer with mutations in the epidermal growth factor receptor: A scoping review. Crit Rev Oncol Hematol 2024; 194:104246. [PMID: 38135018 DOI: 10.1016/j.critrevonc.2023.104246] [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: 09/22/2023] [Revised: 12/16/2023] [Accepted: 12/18/2023] [Indexed: 12/24/2023] Open
Abstract
Non-Small Cell Lung Cancer (NSCLC) represents ∼85% of all lung cancers and ∼15-20% of them are characterized by mutations affecting the Epidermal Growth Factor Receptor (EGFR). For several years now, a class of tyrosine kinase inhibitors was developed, targeting sensitive mutations affecting the EGFR (EGFR-TKIs). To date, the main burden of the TKIs employment is due to the onset of resistance mutations. This scoping review aims to resume the current situation about the cell line models employed for the in vitro evaluation of resistance mechanisms induced by EGFR-TKIs in oncogene-addicted NSCLC. Adenocarcinoma results the most studied NSCLC histotype with the H1650, H1975, HCC827 and PC9 mutated cell lines, while Gefitinib and Osimertinib the most investigated inhibitors. Overall, data collected frame the current advancement of this topic, showing a plethora of approaches pursued to overcome the TKIs resistance, from RNA-mediated strategies to the innovative combination therapies.
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Affiliation(s)
- Alessia Belloni
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | - Armanda Pugnaloni
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | - Maria Rita Rippo
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | - Silvia Di Valerio
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | - Chiara Giordani
- Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences on Ageing (IRCCS INRCA), Ancona, Italy
| | - Antonio Domenico Procopio
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy; Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences on Ageing (IRCCS INRCA), Ancona, Italy
| | - Giuseppe Bronte
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy; Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences on Ageing (IRCCS INRCA), Ancona, Italy.
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Patil T, Staley A, Nie Y, Sakamoto M, Stalker M, Jurica JM, Koehler K, Cass A, Kuykendall H, Schmitt E, Filar E, Reventaite E, Davies KD, Nijmeh H, Haag M, Yoder BA, Bunn PA, Schenk EL, Aisner DL, Iams WT, Marmarelis ME, Camidge DR. The Efficacy and Safety of Treating Acquired MET Resistance Through Combinations of Parent and MET Tyrosine Kinase Inhibitors in Patients With Metastatic Oncogene-Driven NSCLC. JTO Clin Res Rep 2024; 5:100637. [PMID: 38361741 PMCID: PMC10867444 DOI: 10.1016/j.jtocrr.2024.100637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/11/2024] [Accepted: 01/14/2024] [Indexed: 02/17/2024] Open
Abstract
Introduction Acquired MET gene amplification, MET exon 14 skip mutations, or MET fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized. Methods Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease. Results Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%). Conclusions The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.
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Affiliation(s)
- Tejas Patil
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Alyse Staley
- University of Colorado Cancer Center Biostatistics Core, University of Colorado School of Medicine, Aurora, Colorado
| | - Yunan Nie
- Department of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut
| | - Mandy Sakamoto
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Margaret Stalker
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - James M. Jurica
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Kenna Koehler
- Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
| | - Amanda Cass
- Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
| | - Halle Kuykendall
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Emily Schmitt
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Emma Filar
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Evelina Reventaite
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Kurt D. Davies
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Hala Nijmeh
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Mary Haag
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Benjamin A. Yoder
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Paul A. Bunn
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Erin L. Schenk
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Dara L. Aisner
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Wade T. Iams
- Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
| | - Melina E. Marmarelis
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - D. Ross Camidge
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
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10
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Yuan P, Xue X, Qiu T, Ying J. MET alterations detection platforms and clinical implications in solid tumors: a comprehensive review of literature. Ther Adv Med Oncol 2024; 16:17588359231221910. [PMID: 38249331 PMCID: PMC10798113 DOI: 10.1177/17588359231221910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 12/04/2023] [Indexed: 01/23/2024] Open
Abstract
MET alterations, including MET exon 14 skipping variants, MET amplification, MET overexpression, and MET fusion, play pivotal roles in primary tumorigenesis and acquired resistance to targeted therapies, especially EGFR tyrosine kinase inhibitors. They represent important diagnostic, prognostic, and predictive biomarkers in many solid tumor types. However, the detection of MET alterations is challenging due to the complexity of MET alterations and the diversity of platform technologies. Therefore, techniques with high sensitivity, specificity, and reliable molecular detection accuracy are needed to overcome such hindrances and aid in biomarker-guided therapies. The current review emphasizes the role of MET alterations as oncogenic drivers in a variety of cancers and their involvement in the development of resistance to targeted therapies. Moreover, our review provides an overview of and recommendations on the selection of various cross-platform technologies for the detection of MET exon 14 skipping variants, MET amplification, MET overexpression, and MET fusion. Furthermore, challenges and hurdles underlying these common detection platforms are discussed.
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Affiliation(s)
- Pei Yuan
- Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuemin Xue
- Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tian Qiu
- Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianming Ying
- Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
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11
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Guo X, Wu Y, Xue Y, Xie N, Shen G. Revolutionizing cancer immunotherapy: unleashing the potential of bispecific antibodies for targeted treatment. Front Immunol 2023; 14:1291836. [PMID: 38106416 PMCID: PMC10722299 DOI: 10.3389/fimmu.2023.1291836] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/08/2023] [Indexed: 12/19/2023] Open
Abstract
Recent progressions in immunotherapy have transformed cancer treatment, providing a promising strategy that activates the immune system of the patient to find and eliminate cancerous cells. Bispecific antibodies, which engage two separate antigens or one antigen with two distinct epitopes, are of tremendous concern in immunotherapy. The bi-targeting idea enabled by bispecific antibodies (BsAbs) is especially attractive from a medical standpoint since most diseases are complex, involving several receptors, ligands, and signaling pathways. Several research look into the processes in which BsAbs identify different cancer targets such angiogenesis, reproduction, metastasis, and immune regulation. By rerouting cells or altering other pathways, the bispecific proteins perform effector activities in addition to those of natural antibodies. This opens up a wide range of clinical applications and helps patients with resistant tumors respond better to medication. Yet, further study is necessary to identify the best conditions where to use these medications for treating tumor, their appropriate combination partners, and methods to reduce toxicity. In this review, we provide insights into the BsAb format classification based on their composition and symmetry, as well as the delivery mode, focus on the action mechanism of the molecule, and discuss the challenges and future perspectives in BsAb development.
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Affiliation(s)
- Xiaohan Guo
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Yi Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Ying Xue
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Na Xie
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Guobo Shen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
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12
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Shiraishi T, Yamasaki K, Kidogawa M, Shingu T, Ujimiya F, Jotatsu T, Matsumoto S, Izumi H, Nishida C, Goto K, Yatera K. Successful Treatment with Crizotinib to Overcome Drug Resistance Possibly Due to Mesenchymal-epithelial Transition Amplification in a Lung Cancer Patient with the Echinoderm Microtubule-associated Protein-like 4-anaplastic Lymphoma Kinase Fusion Gene. Intern Med 2023; 62:3215-3221. [PMID: 36927974 PMCID: PMC10686730 DOI: 10.2169/internalmedicine.1164-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 01/11/2023] [Indexed: 03/15/2023] Open
Abstract
Amplification of the mesenchymal-epithelial transition (MET) gene plays an important role in anticancer drug resistance to anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-rearranged lung cancer cells. We encountered an ALK-rearranged lung cancer patient who developed MET amplification after alectinib treatment and showed an effective response to fifth-line crizotinib. First-line alectinib treatment was effective for 2.5 years; however, liver metastases exacerbated. Liver biopsy specimens revealed MET and human epidermal growth factor receptor 2 (HER2) amplifications. Switching to the MET inhibitor crizotinib improved liver metastases. Crizotinib may be effective in ALK-positive patients with MET amplification.
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Affiliation(s)
- Tomoko Shiraishi
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Kei Yamasaki
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Moe Kidogawa
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Tatsuya Shingu
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Fuki Ujimiya
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Takanobu Jotatsu
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Shingo Matsumoto
- Department of Thoracic Oncology, National Cancer Center Hospital East, Japan
| | - Hiroki Izumi
- Department of Thoracic Oncology, National Cancer Center Hospital East, Japan
| | - Chinatsu Nishida
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Koichi Goto
- Department of Thoracic Oncology, National Cancer Center Hospital East, Japan
| | - Kazuhiro Yatera
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
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13
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Urbanska EM, Grauslund M, Koffeldt PR, Truelsen SLB, Löfgren JO, Costa JC, Melchior LC, Sørensen JB, Santoni-Rugiu E. Real-World Data on Combined EGFR-TKI and Crizotinib Treatment for Acquired and De Novo MET Amplification in Patients with Metastatic EGFR-Mutated NSCLC. Int J Mol Sci 2023; 24:13077. [PMID: 37685884 PMCID: PMC10487649 DOI: 10.3390/ijms241713077] [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: 07/30/2023] [Revised: 08/15/2023] [Accepted: 08/19/2023] [Indexed: 09/10/2023] Open
Abstract
Amplification of the mesenchymal epithelial transition (MET) gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced EGFR-mutated (EGFRm+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2-8% of EGFRm+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these MET amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level MET amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of MET amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing MET amplification. Additionally, we addressed the issue of managing EGFR-mutated NSCLC patients with de novo MET amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring MET amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3-19 months.
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Affiliation(s)
- Edyta M. Urbanska
- Department of Oncology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark;
| | - Morten Grauslund
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark; (M.G.); (P.R.K.); (S.L.B.T.); (L.C.M.)
| | - Peter R. Koffeldt
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark; (M.G.); (P.R.K.); (S.L.B.T.); (L.C.M.)
| | - Sarah L. B. Truelsen
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark; (M.G.); (P.R.K.); (S.L.B.T.); (L.C.M.)
| | - Johan O. Löfgren
- Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark;
| | - Junia C. Costa
- Department of Radiology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark;
| | - Linea C. Melchior
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark; (M.G.); (P.R.K.); (S.L.B.T.); (L.C.M.)
| | - Jens B. Sørensen
- Department of Oncology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark;
- Department of Clinical Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Eric Santoni-Rugiu
- Department of Pathology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark; (M.G.); (P.R.K.); (S.L.B.T.); (L.C.M.)
- Department of Clinical Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark
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14
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Cecchi F, Rex K, Schmidt J, Vocke CD, Lee YH, Burkett S, Baker D, Damore MA, Coxon A, Burgess TL, Bottaro DP. Rilotumumab Resistance Acquired by Intracrine Hepatocyte Growth Factor Signaling. Cancers (Basel) 2023; 15:460. [PMID: 36672409 PMCID: PMC9857108 DOI: 10.3390/cancers15020460] [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: 12/05/2022] [Revised: 01/04/2023] [Accepted: 01/06/2023] [Indexed: 01/13/2023] Open
Abstract
Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of MET and HGF genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention.
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Affiliation(s)
- Fabiola Cecchi
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Karen Rex
- Amgen, Inc., Thousand Oaks, CA 91320, USA
| | | | - Cathy D. Vocke
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Young H. Lee
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sandra Burkett
- Molecular Cytogenetics Core Facility, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
| | | | | | | | | | - Donald P. Bottaro
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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15
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Lin S, Ruan H, Qin L, Zhao C, Gu M, Wang Z, Liu B, Wang H, Wang J. Acquired resistance to EGFR-TKIs in NSCLC mediates epigenetic downregulation of MUC17 by facilitating NF-κB activity via UHRF1/DNMT1 complex. Int J Biol Sci 2023; 19:832-851. [PMID: 36778111 PMCID: PMC9910003 DOI: 10.7150/ijbs.75963] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 12/09/2022] [Indexed: 01/12/2023] Open
Abstract
Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has brought significant benefits to non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, most patients eventually develop acquired resistance after treatment. This study investigated the epigenetic effects of mucin 17 (MUC17) in acquired drug-resistant cells of EGFR-TKIs. We found that GR/OR (gefitinib/osimertinib-resistance) cells enhance genome-wide DNA hypermethylation, mainly in 5-UTR associated with multiple oncogenic pathways, in which GR/OR cells exerted a pro-oncogenic effect by downregulating mucin 17 (MUC17) expression in a dose- and time-dependent manner. Gefitinib/osimertinib acquired resistance mediated down-regulation of MUC17 by promoting DNMT1/UHRF1 complex-dependent promoter methylation, thereby activating NF-κB activity. MUC17 increased the generation of IκB-α and inhibit NF-κB activity by promoting the expression of MZF1. In vivo results also showed that DNMT1 inhibitor (5-Aza) in combination with gefitinib/osimertinib restored sensitivity to OR/GR cells. Acquired drug resistance of gefitinib/osimertinib promoted UHRF1/DNMT1 complex to inhibit the expression of MUC17. MUC17 in GR/OR cells may act as an epigenetic sensor for biomonitoring the resistance to EGFR-TKIs.
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Affiliation(s)
- Shuye Lin
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
| | - Hongyun Ruan
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
| | - Lin Qin
- Department of Endoscopic Diagnosis and Treatment, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing 101149, China
| | - Cong Zhao
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
| | - Meng Gu
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
| | - Ziyu Wang
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
| | - Bin Liu
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
| | - Haichao Wang
- Institute of Resources and Environment, Beijing Academy of Science and Technology, Beijing, 100089, China
| | - Jinghui Wang
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
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16
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Moiseenko F, Bogdanov A, Egorenkov V, Volkov N, Moiseyenko V. Management and Treatment of Non-small Cell Lung Cancer with MET Alteration and Mechanisms of Resistance. Curr Treat Options Oncol 2022; 23:1664-1698. [PMID: 36269457 DOI: 10.1007/s11864-022-01019-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2022] [Indexed: 01/30/2023]
Abstract
OPINION STATEMENT MET-driven tumors are a heterogenous group of non-small cell lung cancers (NSCLC) with activating mutations. Pathologic activation of MET can be achieved with increased number of gene copies overexpression, or decreased protein degradation through several mechanisms, including mutations, amplifications, or fusions. Besides its role as primary driver, MET activation might also mediate resistance to kinase inhibitors in NSCLC with various other actionable alterations. While checkpoint inhibitors have modest efficacy in MET-driven tumors, several approaches of targeted blockade are available. Among them the most promising are small tyrosine kinase inhibitors, antibody-drug conjugates, and bispecific antibodies. Unfortunately, resistance is virtually inevitable. Resistance to small kinase inhibitors might be mediated by kinase domain mutations or activation of shunting cascades. Various resistance mechanisms might be present in one patient, making it overcoming an unresolved problem.
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Affiliation(s)
- Fedor Moiseenko
- Saint-Petersburg City Cancer Center, Leningradskay 68a, Lit.A, Pesochny, St. Petersburg, 197758, Russia. .,N.N. Petrov National Medical Research Center of Oncology, Ministry of Public Health of the Russian Federation, 68, Leningradskaya st., Pesochny, St. Petersburg, 197758, Russia. .,State Budget Institution of Higher Education "North-Western State Medical University named after I.I Mechnikov" under the Ministry of Public Health of the Russian Federation, 41, Kirochnaya str, Saint Petersburg, 191015, Russia.
| | - Alexey Bogdanov
- Saint-Petersburg City Cancer Center, Leningradskay 68a, Lit.A, Pesochny, St. Petersburg, 197758, Russia
| | - Vitaliy Egorenkov
- Saint-Petersburg City Cancer Center, Leningradskay 68a, Lit.A, Pesochny, St. Petersburg, 197758, Russia
| | - Nikita Volkov
- Saint-Petersburg City Cancer Center, Leningradskay 68a, Lit.A, Pesochny, St. Petersburg, 197758, Russia
| | - Vladimir Moiseyenko
- Saint-Petersburg City Cancer Center, Leningradskay 68a, Lit.A, Pesochny, St. Petersburg, 197758, Russia
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17
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Lai GGY, Guo R, Drilon A, Shao Weng Tan D. Refining patient selection of MET-activated non-small cell lung cancer through biomarker precision. Cancer Treat Rev 2022; 110:102444. [PMID: 36108503 PMCID: PMC10961969 DOI: 10.1016/j.ctrv.2022.102444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 07/21/2022] [Accepted: 07/28/2022] [Indexed: 12/12/2022]
Abstract
Dysregulated MET signaling plays an important role in lung oncogenesis, tumor growth and invasiveness. It may occur through various mechanisms, such as MET overexpression or gene amplification or mutation, all of which can be detected by specific methods. The utility of MET overexpression as a biomarker remains unclear due to discrepancies in its occurrence and non-standardized cut-off thresholds. MET exon 14 skipping mutation (METex14) was established as a strong predictor of response to selective MET tyrosine kinase inhibitors (TKIs), and clinical trial results in patients with non-small cell lung cancer (NSCLC) harboring METex14 led to the approval of capmatinib and tepotinib by regulatory agencies worldwide. MET amplification is an emerging biomarker, with clinical data indicating an association between MET gene copy number and response to MET-TKIs. Additionally, MET amplification represents an important mechanism of resistance to TKIs in oncogene-driven NSCLC. The identification of molecular alterations for which targeted therapies are available is important, and high-throughput next-generation sequencing techniques can provide information on multiple genes at the same time, helping to provide valuable predictive information for oncogene-driven cancers. This review summarizes the current methods used for the detection of METex14, MET amplification and MET overexpression, and discusses the evidence for the use of MET-TKIs in patients with NSCLC with MET dysregulation. We discuss the practical challenges that impact the use of METex14 in the clinic and the evidence gaps that need to be addressed to validate additional genomic markers for MET-dependent cancers.
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Affiliation(s)
- Gillianne G Y Lai
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Robin Guo
- Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA
| | - Alexander Drilon
- Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA
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Zhang Y, Huang X, Niu R, Li C, Pang J, Liu P, Adachi H, Kawase A, Yamaguchi F, Du Y. Association between EGFR gene mutant protein expression and T790M mutation after first-generation EGFR-TKI treatment resistance: a retrospective, single-arm clinical study. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:935. [PMID: 36172116 PMCID: PMC9511196 DOI: 10.21037/atm-22-3850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/30/2022] [Indexed: 11/12/2022]
Abstract
Background Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is an important treatment for lung adenocarcinoma patients with EGFR gene mutations. The purpose of this study was to review the efficacy of first-generation EGFR-TKIs and the incidence of T790M after first-generation TKI resistance in stage IV lung adenocarcinoma patients with positive EGFR gene mutation expression associated with EGFR mutant protein. Methods Tumor tissues were collected from stage IV lung adenocarcinoma patients with EGFR gene mutation who received first-generation EGFR-TKI targeted therapy. Patients were followed up through outpatient and inpatient systems. Immunohistochemistry was used to detect the expression of corresponding EGFR mutant protein in tumor tissues. The incidence of T790M mutation after first-generation TKI resistance and the correlation between the mutant protein and progression-free survival (PFS) after first-generation TKI treatment were investigated. Results T790M mutation rates were 37.93% (11/29) and 42.50% (17/40) in the EGFR mutation groups, respectively, after first-generation TKI treatment for drug resistance. In patients with exon 19 deletion, T790M mutations were found in 63.64% (7/11) of patients with positive protein expression and 22.22% (4/18) of patients with negative protein expression (P=0.026; χ2=4.974). The mutation rate of T790M after drug resistance in patients with L858R mutation was 53.57% (15/28) and 16.67% (2/12) in the protein expression-positive and negative groups, respectively (χ2=4.682, P=0.030). The variations were statistically significant. Conclusions After resistance to the first-generation EGFR-TKI treatment, the occurrence of T790M mutation may be related to the expression of EGFR mutant protein in patients with EGFR gene mutation.
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Affiliation(s)
- Yiruo Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xin Huang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ruiqi Niu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chenghui Li
- Department of Oncology, Anqing Municipal Hospital, Anqing, China
| | - Jingdan Pang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Pingping Liu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hiroyuki Adachi
- Department of Thoracic Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Akikazu Kawase
- First Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Fumihiro Yamaguchi
- Department of Respiratory Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Yingying Du
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Vaquero J, Pavy A, Gonzalez-Sanchez E, Meredith M, Arbelaiz A, Fouassier L. Genetic alterations shaping tumor response to anti-EGFR therapies. Drug Resist Updat 2022; 64:100863. [DOI: 10.1016/j.drup.2022.100863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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He X, Wang Y, Zou C, Zheng C, Luo Y, Zhou Y, Tu C. Case Report: Gene Heterogeneity in the Recurrent and Metastatic Lesions of a Myxoid Chondrosarcoma Patient With Aggressive Transformation. Front Genet 2022; 13:791675. [PMID: 35910216 PMCID: PMC9330136 DOI: 10.3389/fgene.2022.791675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 06/23/2022] [Indexed: 11/29/2022] Open
Abstract
Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma. In view of the indolent course throughout the prolonged natural history of EMC, it was considered as a low-grade soft-tissue sarcoma. However, recent studies have revealed a high recurrence and metastatic potential in EMC, and the invasiveness of EMC may progress during the protracted clinical course. The mechanism for this aggressive transformation remains unknown. Here, we present a rare case of EMC with aggressive behavior. This case was confirmed via pathology and NR4A3 fluorescent in situ hybridization. To verify the genetic characteristics of this rare case, a total gene sequencing analyses was performed in the recurrent and metastatic lesions. Intriguingly, different gene mutations were determined in the recurrent and metastatic lesions, which implied the genetic heterogeneity among the different lesions might be related to the aggressiveness of EMC. Furthermore, we discuss a few potential agents against the mutated genes in this case, which may provide novel insights regarding the targeted therapy of EMC.
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Affiliation(s)
- Xuanhong He
- Department of Orthopedics, Orthopedics Research Institute, West China Hospital, Sichuan University, Chengdu, China
- Bone and Joint 3D-Printing & Biomechanical Laboratory, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Yitian Wang
- Department of Orthopedics, Orthopedics Research Institute, West China Hospital, Sichuan University, Chengdu, China
- Bone and Joint 3D-Printing & Biomechanical Laboratory, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Chang Zou
- Department of Orthopedics, Orthopedics Research Institute, West China Hospital, Sichuan University, Chengdu, China
- Bone and Joint 3D-Printing & Biomechanical Laboratory, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Chuanxi Zheng
- Department of Orthopedics, Orthopedics Research Institute, West China Hospital, Sichuan University, Chengdu, China
- Bone and Joint 3D-Printing & Biomechanical Laboratory, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Luo
- Department of Orthopedics, Orthopedics Research Institute, West China Hospital, Sichuan University, Chengdu, China
- Bone and Joint 3D-Printing & Biomechanical Laboratory, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Yong Zhou
- Department of Orthopedics, Orthopedics Research Institute, West China Hospital, Sichuan University, Chengdu, China
- Bone and Joint 3D-Printing & Biomechanical Laboratory, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Chongqi Tu
- Department of Orthopedics, Orthopedics Research Institute, West China Hospital, Sichuan University, Chengdu, China
- Bone and Joint 3D-Printing & Biomechanical Laboratory, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Chongqi Tu,
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21
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Xu T, Wang X, Wang Z, Deng T, Qi C, Liu D, Li Y, Ji C, Li J, Shen L. Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors. Ther Adv Med Oncol 2022; 14:17588359221105022. [PMID: 35747165 PMCID: PMC9210093 DOI: 10.1177/17588359221105022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 05/16/2022] [Indexed: 11/16/2022] Open
Abstract
Background Combinatorial inhibition of epidermal growth factor receptor (EGFR) and BRAF shows remarkable clinical benefits in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). However, the tumor may inevitably develop resistance to the targeted therapy, thereby limiting the response rate and durability. This study aimed to determine the genetic alterations associated with intrinsic and acquired resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Methods Targeted sequencing of 520 cancer-related genes was performed in tumor tissues and in plasma samples collected from patients with BRAF V600E-mutant mCRC, who were treated with EGFR/BRAF ± MEK inhibitors, before and after the targeted treatment. Clinical benefit was defined as an objective response or a stable disease lasting longer than the median progression-free survival (PFS). Results In all, 25 patients with BRAF V600E-mutant mCRC were included in this study. Those with RNF43 mutations (n = 8) were more likely to achieve clinical benefit from EGFR/BRAF inhibitors than those with wild-type RNF43 (87.5% versus 37.5%, p = 0.034). Genetic alterations in receptor tyrosine kinase genes (n = 6) were associated with worse PFS (p = 0.005). Among the 23 patients whose disease progressed after the EGFR/BRAF-targeted therapy, at least one acquired resistance-related mutation was detected in 12 patients. Acquired mutations were most frequently observed in the mitogen-activated protein kinase pathway-related genes (n = 9), including KRAS (G12D and Q61H/R), NRAS (Q61L/R/K and amplification), BRAF (amplification), and MEK1 (K57T). MET amplification and PIK3R1 Q579fs mutation emerged in three patients and one patient, respectively, after disease progression. Conclusion Multiple genetic alterations are associated with clinical benefits and resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Our findings provide novel insights into strategies for overcoming resistance to EGFR/BRAF inhibitors in patients with BRAF V600E-mutant mCRC.
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Affiliation(s)
- Ting Xu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xicheng Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhenghang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ting Deng
- National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Changsong Qi
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Dan Liu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yanyan Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Congcong Ji
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing 100142, China
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NSCLC as the Paradigm of Precision Medicine at Its Finest: The Rise of New Druggable Molecular Targets for Advanced Disease. Int J Mol Sci 2022; 23:ijms23126748. [PMID: 35743191 PMCID: PMC9223783 DOI: 10.3390/ijms23126748] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/09/2022] [Accepted: 06/14/2022] [Indexed: 02/04/2023] Open
Abstract
Standard treatment for advanced non-small cell lung cancer (NSCLC) historically consisted of systemic cytotoxic chemotherapy until the early 2000s, when precision medicine led to a revolutionary change in the therapeutic scenario. The identification of oncogenic driver mutations in EGFR, ALK and ROS1 rearrangements identified a subset of patients who largely benefit from targeted agents. However, since the proportion of patients with druggable alterations represents a minority, the discovery of new potential driver mutations is still an urgent clinical need. We provide a comprehensive review of the emerging molecular targets in NSCLC and their applications in the advanced setting.
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Floresta G, Abbate V. Recent progress in the imaging of c-Met aberrant cancers with positron emission tomography. Med Res Rev 2022; 42:1588-1606. [PMID: 35292998 PMCID: PMC9314990 DOI: 10.1002/med.21885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 01/31/2022] [Accepted: 02/22/2022] [Indexed: 11/06/2022]
Abstract
Tyrosine-protein kinase Met-also known as c-Met or HGFR-is a membrane receptor protein with associated tyrosine kinase activity physiologically stimulated by its natural ligand, the hepatocyte growth factor (HGF), and is involved in different ways in cancer progression and tumourigenesis. Targeting c-Met with pharmaceuticals has been preclinically proved to have significant benefits for cancer treatment. Recently, evaluating the protein status during and before c-Met targeted therapy has been shown of relevant importance by different studies, demonstrating that there is a correlation between the status (e.g., aberrant activation and overexpression) of the HGFR with therapy response and clinical prognosis. Currently, clinical imaging based on positron emission tomography (PET) appears as one of the most promising tools for the in vivo real-time scanning of irregular alterations of the tyrosine-protein kinase Met and for the diagnosis of c-Met related cancers. In this study, we review the recent progress in the imaging of c-Met aberrant cancers with PET. Particular attention is directed on the development of PET probes with a range of different sizes (HGF, antibodies, anticalines, peptides, and small molecules), and radiolabeled with different radionuclides. The goal of this review is to report all the preclinical imaging studies based on PET imaging reported until now for in vivo diagnosis of c-Met in oncology to support the design of novel and more effective PET probes for in vivo evaluation of c-Met.
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Affiliation(s)
- Giuseppe Floresta
- Department of Analytical, Environmental and Forensic Sciences, Institute of Pharmaceutical Sciences, King's College London, London, UK
| | - Vincenzo Abbate
- Department of Analytical, Environmental and Forensic Sciences, Institute of Pharmaceutical Sciences, King's College London, London, UK
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Sitthideatphaiboon P, Teerapakpinyo C, Korphaisarn K, Leelayuwatanakul N, Pornpatrananrak N, Poungvarin N, Chantranuwat P, Shuangshoti S, Aporntewan C, Chintanapakdee W, Sriuranpong V, Vinayanuwattikun C. Co-occurrence CDK4/6 amplification serves as biomarkers of de novo EGFR TKI resistance in sensitizing EGFR mutation non-small cell lung cancer. Sci Rep 2022; 12:2167. [PMID: 35140316 PMCID: PMC8828869 DOI: 10.1038/s41598-022-06239-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 01/17/2022] [Indexed: 12/19/2022] Open
Abstract
Despite the development of predictive biomarkers to shape treatment paradigms and outcomes, de novo EGFR TKI resistance advanced non-small cell lung cancer (NSCLC) remains an issue of concern. We explored clinical factors in 332 advanced NSCLC who received EGFR TKI and molecular characteristics through 65 whole exome sequencing of various EGFR TKI responses including; de novo (progression within 3 months), intermediate response (IRs) and long-term response (LTRs) (durability > 2 years). Uncommon EGFR mutation subtypes were significantly variable enriched in de novo resistance. The remaining sensitizing EGFR mutation subtypes (exon 19 del and L858R) accounted for 75% of de novo resistance. Genomic landscape analysis was conducted, focusing in 10 frequent oncogenic signaling pathways with functional contributions; cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF-β, p53 and β-catenin/Wnt signaling. Cell cycle pathway was the only significant alteration pathway among groups with the FDR p-value of 6 × 10-4. We found only significant q-values of < 0.05 in 7 gene alterations; CDK6, CCNE1, CDK4, CCND3, MET, FGFR4 and HRAS which enrich in de novo resistance [range 36-73%] compared to IRs/LTRs [range 4-22%]. Amplification of CDK4/6 was significant in de novo resistance, contrary to IRs and LTRs (91%, 27.9% and 0%, respectively). The presence of co-occurrence CDK4/6 amplification correlated with poor disease outcome with HR of progression-free survival of 3.63 [95% CI 1.80-7.31, p-value < 0.001]. The presence of CDK4/6 amplification in pretreatment specimen serves as a predictive biomarker for de novo resistance in sensitizing EGFR mutation.
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Affiliation(s)
- Piyada Sitthideatphaiboon
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand
| | - Chinachote Teerapakpinyo
- Chula GenePRO Center, Research Affairs, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand
| | - Krittiya Korphaisarn
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Siriraj, Bangkok Noi, Bangkok, 10700, Thailand
| | - Nophol Leelayuwatanakul
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Nopporn Pornpatrananrak
- Department of Surgery, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand
| | - Naravat Poungvarin
- Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Siriraj, Bangkok Noi, Bangkok, 10700, Thailand
| | - Poonchavist Chantranuwat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand
| | - Shanop Shuangshoti
- Chula GenePRO Center, Research Affairs, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand.,Department of Pathology, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand
| | - Chatchawit Aporntewan
- Department of Mathematics and Computer Science & Omics Science and Bioinformatics Center, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Wariya Chintanapakdee
- Department of Radiology, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Virote Sriuranpong
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand
| | - Chanida Vinayanuwattikun
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand.
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Wang A, Yang W, Li Y, Zhang Y, Zhou J, Zhang R, Zhang W, Zhu J, Zeng Y, Liu Z, Huang JA. CPNE1 promotes non-small cell lung cancer progression by interacting with RACK1 via the MET signaling pathway. Cell Commun Signal 2022; 20:16. [PMID: 35101055 PMCID: PMC8802424 DOI: 10.1186/s12964-021-00818-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 12/06/2021] [Indexed: 12/14/2022] Open
Abstract
Background Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the most lethal tumour worldwide. Copine 1 (CPNE1) was identified as a novel oncogene in NSCLC in our previous study. However, its specific function and relative mechanisms remain poorly understood. Methods The biological role of CPNE1 and RACK1 in NSCLC was investigated using gene expression knockdown and overexpression, cell proliferation assays, clonogenic assays, and Transwell assays. The expression levels of CPNE1, RACK1 and other proteins were determined by western blot analysis. The relationship between CPNE1 and RACK1 was predicted and investigated by mass spectrometry analysis, immunofluorescence staining, and coimmunoprecipitation. NSCLC cells were treated with a combination of a MET inhibitor and gefitinib in vitro and in vivo. Results We found that CPNE1 facilitates tumorigenesis in NSCLC by interacting with RACK1, which further induces activation of MET signaling. CPNE1 overexpression promoted cell proliferation, migration, invasion and MET signaling in NSCLC cells, whereas CPNE1 knockdown produced the opposite effects. In addition, the suppression of the enhancing effect of CPNE1 overexpression on tumorigenesis and MET signaling by knockdown of RACK1 was verified. Moreover, compared to single-agent treatment, dual blockade of MET and EGFR resulted in enhanced reductions in the tumour volume and downstream signaling in vivo. Conclusions Our findings show that CPNE1 promotes tumorigenesis by interacting with RACK1 and activating MET signaling. The combination of a MET inhibitor with an EGFR-TKI attenuated tumour growth more significantly than either single-drug treatment. These findings may provide new insights into the biological function of CPNE1 and the development of novel therapeutic strategies for NSCLC.
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