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Li JX, Li RZ, Ma LR, Wang P, Xu DH, Huang J, Li LQ, Tang L, Xie Y, Leung ELH, Yan PY. Targeting Mutant Kirsten Rat Sarcoma Viral Oncogene Homolog in Non-Small Cell Lung Cancer: Current Difficulties, Integrative Treatments and Future Perspectives. Front Pharmacol 2022; 13:875330. [PMID: 35517800 PMCID: PMC9065471 DOI: 10.3389/fphar.2022.875330] [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: 02/14/2022] [Accepted: 04/04/2022] [Indexed: 11/15/2022] Open
Abstract
In the past few decades, several gene mutations, including the anaplastic lymphoma kinase, epidermal growth factor receptor, ROS proto-oncogene 1 and rat sarcoma viral oncogene homolog (RAS), have been discovered in non-small cell lung cancer (NSCLC). Kirsten rat sarcoma viral oncogene homolog (KRAS) is the isoform most frequently altered in RAS-mutated NSCLC cases. Due to the structural and biochemical characteristics of the KRAS protein, effective approaches to treating KRAS-mutant NSCLC still remain elusive. Extensive recent research on KRAS-mutant inhibitors has made a breakthrough in identifying the covalent KRASG12C inhibitor as an effective agent for the treatment of NSCLC. This review mainly concentrated on introducing new covalent KRASG12C inhibitors like sotorasib (AMG 510) and adagrasib (MRTX 849); summarizing inhibitors targeting the KRAS-related upstream and downstream effectors in RAF/MEK/ERK pathway and PI3K/AKT/mTOR pathway; exploring the efficacy of immunotherapy and certain emerging immune-related therapeutics such as adoptive cell therapy and cancer vaccines. These inhibitors are being investigated in clinical trials and have exhibited promising effects. On the other hand, naturally extracted compounds, which have exhibited safe and effective properties in treating KRAS-mutant NSCLC through suppressing the MAPK and PI3K/AKT/mTOR signaling pathways, as well as through decreasing PD-L1 expression in preclinical studies, could be expected to enter into clinical studies. Finally, in order to confront the matter of drug resistance, the ongoing clinical trials in combination treatment strategies were summarized herein.
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Affiliation(s)
- Jia-Xin Li
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Run-Ze Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
| | - Lin-Rui Ma
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Peng Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Dong-Han Xu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Jie Huang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Li-Qi Li
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
| | - Ling Tang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, China
- Guangdong Provincial Engineering Laboratory of Chinese Medicine Preparation Technology, Guangzhou, China
| | - Ying Xie
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
| | - Elaine Lai-Han Leung
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
- Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai, China
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macao, China
| | - Pei-Yu Yan
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, China
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Abstract
KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRAS-related studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications.
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Froesch P, Mark M, Rothschild SI, Li Q, Godar G, Rusterholz C, Oppliger Leibundgut E, Schmid S, Colombo I, Metaxas Y, König D, Sessa C, Gautschi O, Früh M. Binimetinib, pemetrexed and cisplatin, followed by maintenance of binimetinib and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) and KRAS mutations. The phase 1B SAKK 19/16 trial. Lung Cancer 2021; 156:91-99. [PMID: 33933896 DOI: 10.1016/j.lungcan.2021.04.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/28/2021] [Accepted: 04/02/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND KRAS mutations are found in 20-25 % of non-squamous non-small cell lung cancer (NSCLC) and therapies targeting the RAS/MEK/ERK pathway are in development. We performed a multicenter open-label phase 1B trial to determine the recommended phase 2 dose and early antitumor activity of the MEK-inhibitor binimetinib combined with cisplatin and pemetrexed. METHODS Eligible patients (pts) had stage III-IV NSCLC unsuitable for curative treatment, KRAS exon 2 or 3 (codon 12, 13 or 61) mutations, no prior systemic therapy. Pts were enrolled into part 1: 3 + 3 design with dose escalation in 2 dose levels (DL) of binimetinib and part 2: expansion cohort at the maximum tolerated dose (MTD). Pts received 4 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2and binimetinib 30 (DL1)/45 mg (DL2) orally twice a day (bid) d1-14 q3w followed by pemetrexed and binimetinib until progressive disease (PD) or unacceptable toxicity. RESULTS From May 2017 to Dec 2019, 18 pts (13 dose escalation, 5 expansion cohort) were enrolled. Median age was 60 (48-73, range). KRAS mutations were 87.5 % at codon 12. No DLT occurred in the dose escalation cohort. Median number of cycles was 2 (1-17, range). Treatment discontinuation was mainly due to PD (33 %) or pts/physicians' decision (27 %). Together with the expansion cohort, 16 pts were evaluable for safety. Most frequent treatment-related grade 3 AEs were lung infection (25 %), fatigue (19 %), anemia (19 %). Overall response rate among 9 evaluable pts receiving binimetinib at MTD (45 mg bid) was 33 % (7-70 %, 95 % CI). Median progression-free survival was 5.7 months (1.1-14.0, 95 % CI) and overall survival 6.5 months (1.8-NR, 95 % CI). CONCLUSIONS Pts treated with combination of cisplatin, pemetrexed and binimetinib presented no unexpected toxicity. No early signal of increased antitumor activity of binimetinib added to chemotherapy was observed in our pts population.
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Affiliation(s)
- Patrizia Froesch
- Oncology Institute of Southern Switzerland, Via Ospedale, 6500 Bellinzona, Switzerland.
| | - Michael Mark
- Department of Medical Oncology/Hematology, Cantonal Hospital Graubünden, Loëstrasse 170, 7000 Chur, Switzerland.
| | - Sacha I Rothschild
- Department of Medical Oncology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
| | - Qiyu Li
- SAKK Coordinating Center, Effingerstrasse 33, 3008 Bern, Switzerland.
| | - Gilles Godar
- SAKK Coordinating Center, Effingerstrasse 33, 3008 Bern, Switzerland.
| | | | - Elisabeth Oppliger Leibundgut
- Department of Hematology, University Hospital Bern, and Department for BioMedical Research (DBMR), Bern University, 3010 Bern, Switzerland.
| | - Sabine Schmid
- Department of Oncology/Hematology, Cantonal Hospital St.Gallen, Rorschacher Strasse 95, 9007 St.Gallen, Switzerland.
| | - Ilaria Colombo
- Oncology Institute of Southern Switzerland, Via Ospedale, 6500 Bellinzona, Switzerland.
| | - Yannis Metaxas
- Department of Medical Oncology/Hematology, Cantonal Hospital Graubünden, Loëstrasse 170, 7000 Chur, Switzerland.
| | - David König
- Department of Medical Oncology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
| | - Cristiana Sessa
- Oncology Institute of Southern Switzerland, Via Ospedale, 6500 Bellinzona, Switzerland.
| | - Oliver Gautschi
- Medical Oncology, Cantonal Hospital Lucerne, Spitalstrasse, 6004 Lucerne, Switzerland; University of Berne, Hochschulstrasse 6, 3012 Bern, Switzerland.
| | - Martin Früh
- University of Berne, Hochschulstrasse 6, 3012 Bern, Switzerland; Department of Oncology/Hematology, Cantonal Hospital St.Gallen, Rorschacher Strasse 95, 9007 St.Gallen, Switzerland.
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Abstract
Identification of novel therapeutic targets has improved diagnostics and treatment of many diseases. Many innovative treatment strategies have been developed based on the newly identified biomarkers and key molecules. Most of the research focused on ways to manipulate signaling pathways by activating or suppressing them, validate new therapeutic targets for treatment, and epigenetic treatment of diseases. With the identification of aberrations in multiple growth pathways, the focus then shifted to the small molecules involved in these pathways for targeted therapy. In this communication/short review, we highlight the importance of identification of abnormal activation of the mitogen-activated protein kinase (MAPK), ERK1/2, and its upstream mediator MEK1/2, in erythrocytes in patients with sickle cell disease (SCD) critical for the adhesive interactions of these cells with the endothelium, and leukocytes promoting circulatory obstruction leading to tissue ischemia and infraction. We also discuss how targeting this signaling cascade with MEK1/2 inhibitors can reverse acute vasoocclusive crises in SCD.
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Affiliation(s)
- Rahima Zennadi
- Division of Hematology and Duke Comprehensive Sickle Cell Center, Department of Medicine, Duke University Medical Center, North Carolina, USA
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Man RJ, Zhang YL, Jiang AQ, Zhu HL. A patent review of RAF kinase inhibitors (2010–2018). Expert Opin Ther Pat 2019; 29:675-688. [DOI: 10.1080/13543776.2019.1651842] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Ruo-Jun Man
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, People’s Republic of China
- College of Chemistry and Chemical Engineering, Guangxi University for Nationalities, Nanning, People’s Republic of China
| | - Ya-Liang Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, People’s Republic of China
| | - Ai-Qin Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, People’s Republic of China
| | - Hai-Liang Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, People’s Republic of China
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Nakagawa N, Kikuchi K, Yagyu S, Miyachi M, Iehara T, Tajiri T, Sakai T, Hosoi H. Mutations in the RAS pathway as potential precision medicine targets in treatment of rhabdomyosarcoma. Biochem Biophys Res Commun 2019; 512:524-530. [PMID: 30904164 DOI: 10.1016/j.bbrc.2019.03.038] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 03/07/2019] [Indexed: 01/14/2023]
Abstract
Precision medicine strategies for treating rhabdomyosarcoma (RMS), a childhood malignancy, have not been developed. We examined the effect of CH5126766, a potent selective dual RAF/MEK inhibitor, on RMS cell lines. Among the eleven cell lines studied, one NRAS and two HRAS mutated cell lines were detected. CH5126766 inhibited the proliferation and growth in all of the RAS-mutated RMS cell lines, while it induced G1 cell cycle arrest in two of them. G1 cell cycle arrest was accompanied by p21 up-regulation and RB dephosphorylation. CH5126766 also suppressed the in vivo growth of RAS-mutated RMS tumor, and the mice showed improved survival. Thus, our results demonstrate that CH5126766 is an effective RAF/MEK inhibitor in RAS-mutated RMS. This study not only shows that in RMS, mutations in the RAS pathway can be a target for precision medicine, but also demonstrates that the evaluation of the gene mutation status is important in childhood malignancies.
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Affiliation(s)
- Norio Nakagawa
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ken Kikuchi
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Pediatrics, Uji Takeda Hospital, Kyoto, Japan
| | - Shigeki Yagyu
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mitsuru Miyachi
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomoko Iehara
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Tatsuro Tajiri
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiyuki Sakai
- Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hajime Hosoi
- Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Takeuchi Y, Tanaka T, Higashi M, Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T. In vivo effects of short- and long-term MAPK pathway inhibition against neuroblastoma. J Pediatr Surg 2018; 53:2454-2459. [PMID: 30266481 DOI: 10.1016/j.jpedsurg.2018.08.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 08/25/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND/PURPOSE It was reported that almost 80% of relapsed neuroblastomas showed MAPK pathway mutations. In our previous study, both trametinib (MEK inhibitor) and CH5126766 (RAF/MEK inhibitor) showed in vitro antitumor effects on neuroblastoma cells with ERK phosphorylation (pERK). In this study, we analyzed the in vivo effects of MAPK pathway inhibition in neuroblastoma xenografts. METHODS Xenograft mice with IMR5, CHP-212, or SK-N-AS received daily oral administration of either trametinib or CH5126766 for two weeks (short term) or eight weeks (long term). The tumors were measured twice weekly and harvested after treatment for histopathological analyses, including pERK and Ki67 immunohistochemistry. RESULTS In short-term treatment, both inhibitors showed significant growth inhibition in CHP-212 and SK-N-AS xenografts, which were pERK-positive before treatment. The number of pERK- and Ki67-positive cells decreased after treatment. Conversely, IMR5 xenografts, which were pERK-negative, were resistant to treatment. During long-term treatment, SK-N-AS xenografts started to regrow from about six weeks with partial differentiation. pERK-positive cells reincreased in these regrown tumors. CONCLUSIONS MAPK pathway inhibition was effective for treating pERK-positive neuroblastoma in vivo. Therefore, pERK immunohistochemistry might be a convenient biomarker for MAPK pathway inhibition in neuroblastoma treatment. However, neuroblastomas developed acquired drug resistance after long-term treatment. Further studies to overcome acquired resistance are needed.
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Affiliation(s)
- Yuki Takeuchi
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Tomoko Tanaka
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mayumi Higashi
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shigehisa Fumino
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomoko Iehara
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hajime Hosoi
- Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiyuki Sakai
- Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tatsuro Tajiri
- Department of Pediatric Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Srinivas NR. Pharmacology of Pimasertib, A Selective MEK1/2 Inhibitor. Eur J Drug Metab Pharmacokinet 2018; 43:373-382. [PMID: 29488172 DOI: 10.1007/s13318-018-0466-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Pimasertib belongs to the growing family of mitogen activated protein kinase (MEK1/2) inhibitors undergoing clinical development for various cancer indications. Since the MEK inhibition in several cell signalling transduction cascades within tumours was considered therapeutically beneficial, number of clinical investigations of pimasertib have been reported. Despite being orally bioavailable in cancer patients, pimasertib undergoes faster clearance with a short elimination half-life. In addition, due to occurrence of toxicity, the development of pimasertib appears to be stalled. Case studies are provided on the possible utilization of pimasertib in combination therapies with other approved drugs. Based on the review, it appeared that there was the need to identify the optimal dose and the dosing regimen of pimasertib to provide a balance between safety and efficacy when combined with approved therapies.
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Román M, Baraibar I, López I, Nadal E, Rolfo C, Vicent S, Gil-Bazo I. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer 2018; 17:33. [PMID: 29455666 PMCID: PMC5817724 DOI: 10.1186/s12943-018-0789-x] [Citation(s) in RCA: 218] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 02/01/2018] [Indexed: 12/14/2022] Open
Abstract
Lung neoplasms are the leading cause of death by cancer worldwide. Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung malignancies and the majority of patients present advanced disease at onset. However, in the last decade, multiple oncogenic driver alterations have been discovered and each of them represents a potential therapeutic target. Although KRAS mutations are the most frequently oncogene aberrations in lung adenocarcinoma patients, effective therapies targeting KRAS have yet to be developed. Moreover, the role of KRAS oncogene in NSCLC remains unclear and its predictive and prognostic impact remains controversial. The study of the underlying biology of KRAS in NSCLC patients could help to determine potential candidates to evaluate novel targeted agents and combinations that may allow a tailored treatment for these patients. The aim of this review is to update the current knowledge about KRAS-mutated lung adenocarcinoma, including a historical overview, the biology of the molecular pathways involved, the clinical relevance of KRAS mutations as a prognostic and predictive marker and the potential therapeutic approaches for a personalized treatment of KRAS-mutated NSCLC patients.
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Affiliation(s)
- Marta Román
- Department of Oncology, Clínica Universidad de Navarra, 31008, Pamplona, Spain.,Program of Solid Tumors and Biomarkers, Center for Applied Medical Research, Pamplona, Spain
| | - Iosune Baraibar
- Department of Oncology, Clínica Universidad de Navarra, 31008, Pamplona, Spain.,Program of Solid Tumors and Biomarkers, Center for Applied Medical Research, Pamplona, Spain
| | - Inés López
- Program of Solid Tumors and Biomarkers, Center for Applied Medical Research, Pamplona, Spain
| | - Ernest Nadal
- Thoracic Oncology Unit, Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain
| | - Christian Rolfo
- Phase I-Early Clinical Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Edegem, Belgium
| | - Silvestre Vicent
- Program of Solid Tumors and Biomarkers, Center for Applied Medical Research, Pamplona, Spain.,Navarra Health Research Institute (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ignacio Gil-Bazo
- Department of Oncology, Clínica Universidad de Navarra, 31008, Pamplona, Spain. .,Program of Solid Tumors and Biomarkers, Center for Applied Medical Research, Pamplona, Spain. .,Navarra Health Research Institute (IDISNA), Pamplona, Spain. .,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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MEK inhibitors as a novel therapy for neuroblastoma: Their in vitro effects and predicting their efficacy. J Pediatr Surg 2016; 51:2074-2079. [PMID: 27686482 DOI: 10.1016/j.jpedsurg.2016.09.043] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 09/12/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND A recent study reported that relapsed neuroblastomas had frequent RAS-ERK pathway mutations. We herein investigated the effects and pathways of MEK inhibitors, which inhibit the RAS-ERK pathway, as a new molecular-targeted therapy for refractory neuroblastomas. METHOD Five neuroblastoma cell lines were treated with trametinib (MEK inhibitor) or CH5126766 (RAF/MEK inhibitor). Growth inhibition was analyzed using a cell viability assay. ERK phosphorylation and the MYCN expression were analyzed by immunoblotting or immunohistochemistry. RAS/RAF mutations were identified by direct sequencing or through the COSMIC database. RESULTS Both MEK inhibitors showed growth inhibition effects on cells with ERK phosphorylation, but almost no effect on cells without. In immunoblotting analyses, ERK phosphorylation and MYCN expression were suppressed in ERK active cells by these drugs. Furthermore, phosphorylated-ERK immunohistochemistry corresponded to the drug responses. Regarding the relationship between RAS/Raf mutations and ERK phosphorylation, ERK was phosphorylated in one cell line (NLF) without RAS/Raf mutations. CONCLUSION MEK inhibitors are a promising molecular-targeted therapeutic option for ERK active neuroblastomas. The efficacy of MEK inhibitors corresponds to ERK phosphorylation, while RAS/RAF mutations are not always detected in drug-sensitive cells. Phosphorylated-ERK immunohistochemistry is thus a useful method to analyze ERK activity and predict the therapeutic effects of MEK inhibitors.
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Tomasini P, Walia P, Labbe C, Jao K, Leighl NB. Targeting the KRAS Pathway in Non-Small Cell Lung Cancer. Oncologist 2016; 21:1450-1460. [PMID: 27807303 PMCID: PMC5153335 DOI: 10.1634/theoncologist.2015-0084] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 07/29/2016] [Indexed: 12/19/2022] Open
Abstract
: Lung cancer remains the leading cause of cancer-related deaths worldwide. However, significant progress has been made individualizing therapy based on molecular aberrations (e.g., EGFR, ALK) and pathologic subtype. KRAS is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC), found in approximately 30% of lung adenocarcinomas, and is thus an appealing target for new therapies. Although no targeted therapy has yet been approved for the treatment of KRAS-mutant NSCLC, there are multiple potential therapeutic approaches. These may include direct inhibition of KRAS protein, inhibition of KRAS regulators, alteration of KRAS membrane localization, and inhibition of effector molecules downstream of mutant KRAS. This article provides an overview of the KRAS pathway in lung cancer and related therapeutic strategies under investigation. IMPLICATIONS FOR PRACTICE The identification of oncogene-addicted cancers and specific inhibitors has revolutionized non-small cell lung cancer (NSCLC) treatment and outcomes. One of the most commonly mutated genes in adenocarcinoma is KRAS, found in approximately 30% of lung adenocarcinomas, and thus it is an appealing target for new therapies. This review provides an overview of the KRAS pathway and related targeted therapies under investigation in NSCLC. Some of these agents may play a key role in KRAS-mutant NSCLC treatment in the future.
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Affiliation(s)
- Pascale Tomasini
- Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Preet Walia
- Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Catherine Labbe
- Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Kevin Jao
- Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Natasha B Leighl
- Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
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Abstract
Allostery is a regulation at a distance by conveying information from one site to another and an intrinsic property of dynamic proteins. Allostery plays an essential role in receptor trafficking, signal transmission, controlled catalysis, gene turn on/off, or cell apoptosis. Allosteric mutations are considered as one of causes responsible for cancer development, leading to "allosteric diseases" by stabilizing an active or inactive conformation or changing the dynamic distribution of preexisting propagation pathways. The present article mainly focuses on the potential of allosteric therapies for lung cancer. Allosteric drugs may have several advantages over traditional drugs. The epidermal growth factor receptor mutations and signaling pathways downstream (such as PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways) were suggested to play a key role in lung cancer and considered as targets of allosteric therapy. Some allosteric inhibitors for lung cancer-specific targets and a series of preclinical trials of allosteric inhibitors for lung cancer have been developed and reported. We expect that allosteric therapies will gain more attentions to develop combinatorial strategies for lung cancer and metastasis.
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Affiliation(s)
- Ye Ling
- Zhongshan Hospital, Shanghai Institute of Clinical Bioinformatics, Fudan University Center for Clinical Bioinformatics, Biomedical Research Center of Fudan University Zhongshan Hospital, Shanghai, China
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Adjei AA, LoRusso P, Ribas A, Sosman JA, Pavlick A, Dy GK, Zhou X, Gangolli E, Kneissl M, Faucette S, Neuwirth R, Bózon V. A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors. Invest New Drugs 2016; 35:47-58. [PMID: 27650277 PMCID: PMC5306265 DOI: 10.1007/s10637-016-0391-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 09/06/2016] [Indexed: 11/26/2022]
Abstract
Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1–21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2–22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median Tmax was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2–22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46–97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned.
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Affiliation(s)
- Alex A Adjei
- Department of Oncology, Mayo Clinic, 200 First St, SW, Rochester, MN, 55905, USA.
- Roswell Park Cancer Institute, Buffalo, NY, USA.
| | | | - Antoni Ribas
- University of California at Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | | | - Anna Pavlick
- New York University Langone Medical Center, New York, NY, USA
| | - Grace K Dy
- Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Xiaofei Zhou
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Esha Gangolli
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
- AstraZeneca Pharmaceuticals, Waltham, MA, USA
| | - Michelle Kneissl
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Stephanie Faucette
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Rachel Neuwirth
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Viviana Bózon
- Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
- Present address: Array BioPharma Inc., Boulder, CO, USA
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14
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Rosen LS, LoRusso P, Ma WW, Goldman JW, Weise A, Colevas AD, Adjei A, Yazji S, Shen A, Johnston S, Hsieh HJ, Chan IT, Sikic BI. A first-in-human phase I study to evaluate the MEK1/2 inhibitor, cobimetinib, administered daily in patients with advanced solid tumors. Invest New Drugs 2016; 34:604-13. [PMID: 27424159 DOI: 10.1007/s10637-016-0374-3] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 07/03/2016] [Indexed: 12/12/2022]
Abstract
Objective Cobimetinib, a MEK1/2 inhibitor, was administered to patients with advanced solid tumors to assess safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Methods For dose-escalation, a 3 + 3 design was used. Oral cobimetinib was administered once daily on a 21-day on/7-day off (21/7) or a 14-day on/14-day off (14/14) schedule. Serial plasma samples were collected for pharmacokinetic (PK) analysis on Day 1 and at steady state. In expansion stages, patients with RAS or RAF mutant tumors were treated at the maximum tolerated dose (MTD) of the 21/7 or 14/14 schedule. Results Ninety-seven patients received cobimetinib. In the 21/7 dose escalation, 36 patients enrolled in 8 cohorts (0.05 mg/kg-80 mg). Dose-limiting toxicities (DLTs) were Grade 4 hepatic encephalopathy, Grade 3 diarrhea, and Grade 3 rash. In the 14/14 dose escalation, 20 patients enrolled in 4 cohorts (60-125 mg). DLTs were Grade 3 rash and Grade 3 blurred vision associated with presence of reversible subretinal fluid. The MTD was 60 mg on 21/7 schedule and 100 mg on 14/14 schedule. Cobimetinib PK showed dose-proportional increases in exposure. The most frequent adverse events attributed to cobimetinib were diarrhea, rash, fatigue, edema, nausea, and vomiting. In patients treated at the 60-mg (21/7) or 100-mg (14/14) dose, one unconfirmed complete response and 6 confirmed partial responses were observed. All responses occurred in melanoma patients; 6 harbored the BRAF(V600E) mutation. Conclusions Cobimetinib is generally well tolerated and durable responses were observed in BRAF(V600E) mutant melanoma patients. Evaluation of cobimetinib in combination with other therapies is ongoing.
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Affiliation(s)
- Lee S Rosen
- David Geffen School of Medicine, UCLA, 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA, 90404, USA.
| | | | - Wen Wee Ma
- Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Jonathan W Goldman
- David Geffen School of Medicine, UCLA, 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA, 90404, USA
| | - Amy Weise
- Karmanos Cancer Institute, Detroit, MI, USA
| | | | - Alex Adjei
- Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Salim Yazji
- Exelixis, Inc., South San Francisco, CA, USA.,Baxalta, Cambridge, MA, USA
| | - Angela Shen
- Exelixis, Inc., South San Francisco, CA, USA.,Arvinas, New Haven, CT, USA
| | - Stuart Johnston
- Exelixis, Inc., South San Francisco, CA, USA.,Nektar Therapeutics, San Francisco, CA, USA
| | | | - Iris T Chan
- Genentech, Inc., South San Francisco, CA, USA
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15
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Ueyama A, Ban N, Fukazawa M, Hirayama T, Takeda M, Yata T, Muramatsu H, Hoshino M, Yamamoto M, Matsuo M, Kawashima Y, Iwase T, Kitazawa T, Kushima Y, Yamada Y, Kawabe Y. Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance. J Diabetes Res 2016; 2016:8264830. [PMID: 26839898 PMCID: PMC4709921 DOI: 10.1155/2016/8264830] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 09/26/2015] [Accepted: 09/29/2015] [Indexed: 11/18/2022] Open
Abstract
Although mitogen-activated protein kinase kinase (MEK) is a key signaling molecule and a negative regulator of insulin action, it is still uncertain whether MEK can be a therapeutic target for amelioration of insulin resistance (IR) in type 2 diabetes (T2D) in vivo. To clarify whether MEK inhibition improves T2D, we examined the effect of continuous MEK inhibition with two structurally different MEK inhibitors, RO5126766 and RO4987655, in mouse models of T2D. RO5126766 and RO4987655 were administered via dietary admixture. Both compounds decreased blood glucose and improved glucose tolerance in doses sufficient to sustain inhibition of extracellular signal-regulated kinase (ERK)1/2 phosphorylation downstream of MEK in insulin-responsive tissues in db/db mice. A hyperinsulinemic-euglycemic clamp test showed increased glucose infusion rate (GIR) in db/db mice treated with these compounds, and about 60% of the increase was attributed to the inhibition of endogenous glucose production, suggesting that the liver is responsible for the improvement of IR. By means of adenovirus-mediated Mek1 shRNA expression, we confirmed that blood glucose levels are reduced by suppression of MEK1 expression in the liver of db/db mice. Taken together, these results suggested that the MEK signaling pathway could be a novel therapeutic target for novel antidiabetic agents.
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Affiliation(s)
- Atsunori Ueyama
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
- Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, Akita 010-8543, Japan
- *Atsunori Ueyama:
| | - Nobuhiro Ban
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Masanori Fukazawa
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Tohru Hirayama
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Minako Takeda
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Tatsuo Yata
- Chugai Research Institute for Medical Science, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Hiroyasu Muramatsu
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Masaki Hoshino
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Marii Yamamoto
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Masao Matsuo
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Yuka Kawashima
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Tatsuhiko Iwase
- Project Planning & Coordination Department, Chugai Pharmaceutical Co., Ltd., 2-1-1 Nihonbashi, Muromachi, Chuo-ku, Tokyo 103-8324, Japan
| | - Takehisa Kitazawa
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Youichi Kushima
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
| | - Yuichiro Yamada
- Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, Akita 010-8543, Japan
| | - Yoshiki Kawabe
- Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
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16
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Mandal R, Becker S, Strebhardt K. Stamping out RAF and MEK1/2 to inhibit the ERK1/2 pathway: an emerging threat to anticancer therapy. Oncogene 2015; 35:2547-61. [PMID: 26364606 DOI: 10.1038/onc.2015.329] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 07/27/2015] [Accepted: 07/27/2015] [Indexed: 01/04/2023]
Abstract
The RAS-RAF-MEK1/2-ERK1/2 pathway is a key signal transduction pathway in the cells. Critically, it remains constitutively active in approximately 30% of human cancers, having key roles in cancer development, maintenance and progression, while being responsible for poorer prognosis and drug resistance. Consequently, the inhibition of this pathway has been the subject of intense research for >25 years. The advent of better patient screening techniques has increasingly shown that upstream regulators like RAS and RAF remain persistently mutated in many cancer types. These gain-of-function mutations, such as KRAS-4B(G12V/G13D/Q61K), NRAS(Q61L/Q61R) or BRAF(V600E), lead to tremendous increase in their activities, resulting in constitutively active extracellular signal-regulated kinase 1/2 (ERK1/2). They were not efficiently targeted by the first-generation inhibitors such as Lonafarnib or Sorafenib, which were essentially broad spectrum inhibitors targeting pan-RAS and pan-RAF, respectively. This triggered the development of the second-generation inhibitors selective against the mutated proteins. Second generation inhibitors such as Vemurafenib (Zelboraf) and Dabrafenib (Tafinlar) targeting BRAF(V600E), Trametinib (Mekinist) targeting MEK1/2 and the first generation pan-RAF inhibitor Sorafenib (Nexavar) have already been approved for treating renal, hepatocellular, thyroid cancers and BRAF(V600E/K) harboring metastatic melanoma. Others against RAF and MEK1/2 are presently undergoing clinical trials. Their success would depend on the better understanding of the acquired resistance mechanisms to these drugs in the cancer cells and the identification of predictive biomarkers for the proper administration of suitable inhibitor(s).
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Affiliation(s)
- R Mandal
- German Cancer Consortium (DKTK), Heidelberg, Germany.,Department of Gynaecology and Obstetrics, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - S Becker
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - K Strebhardt
- German Cancer Consortium (DKTK), Heidelberg, Germany.,Department of Gynaecology and Obstetrics, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
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17
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Templeton IE, Musib L. MEK inhibitors beyond monotherapy: current and future development. Curr Opin Pharmacol 2015; 23:61-7. [PMID: 26057212 DOI: 10.1016/j.coph.2015.05.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 05/18/2015] [Accepted: 05/19/2015] [Indexed: 10/23/2022]
Abstract
The development of MEK inhibitors has led to improved progression-free survival in patients with mutant BRAF(V600) cancers when used in combination with BRAF inhibitors. However, resistance to combination therapy remains an issue. This review summarizes our current understanding of the role of MEK in cancer cell proliferation and the mechanisms which lead to resistance in patients. Specific adverse events, which have been linked to the MEK inhibitor class, have been described. Future combinations of MEK inhibitors with other cancer therapy options, currently under investigation in clinical trials, are also discussed.
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Affiliation(s)
- Ian E Templeton
- Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA
| | - Luna Musib
- Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA.
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18
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Mizugaki H, Yamamoto N, Fujiwara Y, Nokihara H, Yamada Y, Tamura T. Current Status of Single-Agent Phase I Trials in Japan: Toward Globalization. J Clin Oncol 2015; 33:2051-61. [PMID: 25918301 DOI: 10.1200/jco.2014.58.4953] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE In Japan, phase I trials, except first-in-human trials, are usually initiated from approximately 50% of the maximum-tolerated dose (MTD) or maximum administered dose (MAD) determined during the initial phase I trials in North America and Europe (the West). However, the key findings of phase I trials in Japan and the West, such as dose-limiting toxicity (DLT) profiles and MTD or MAD levels, have not been compared. PATIENTS AND METHODS We retrospectively analyzed data for patients enrolled onto single-agent phase I trials at the National Cancer Center Hospital between 1995 and 2012. DLT profiles, MTDs, and MADs of single-agent phase I trials in Japan were compared with those from trials in the West that were obtained from the literature. RESULTS A total of 777 patients were enrolled onto 54 single-agent phase I trials, including five first-in-human trials. DLTs were observed in 11.1% of the patients. Importantly, 66.4% of the DLTs were observed within a dose range (80% to 120%) similar to those reported for the trials in the West. The majority of MTDs or MADs could be considered similar between patients, and 80.3% of the drugs had similar MTDs or MADs in the West. CONCLUSION The toxicity profiles of single-agent phase I agents determined from trials conducted in Japan were comparable to those obtained from trials in the West. We believe that phase I trials in Japan could be conducted over timelines similar to those in the West, allowing for global or parallel phase I clinical trials.
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19
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Sborov D, Chen JL. Targeted therapy in sarcomas other than GIST tumors. J Surg Oncol 2015; 111:632-40. [PMID: 25330750 PMCID: PMC4436975 DOI: 10.1002/jso.23802] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Accepted: 08/13/2014] [Indexed: 01/01/2023]
Abstract
Non-GIST soft tissue sarcomas are a heterogeneous grouping of mesenchymal tumors that comprise less than 1% of adult malignancies. Treatment continues to be based on cytotoxic chemotherapy regimens. However, characterization of the molecular pathway deregulations that drive these tumors has led to the emergence of more customized treatment options. In this review, we focus on the multitude of molecular inhibitors targeting angiogenesis and cell cycle pathways being tested in clinical trials.
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Affiliation(s)
- Douglas Sborov
- Hematology and Oncology Fellow, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
| | - James L Chen
- Assistant Professor, Departments of Biomedical Informatics and Internal Medicine (Division of Medical Oncology), The Ohio State University, Columbus, OH, USA
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20
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Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors. Invest New Drugs 2015; 33:641-51. [PMID: 25809858 DOI: 10.1007/s10637-015-0229-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 03/05/2015] [Indexed: 10/23/2022]
Abstract
RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg) followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twice-daily dosing (4, 5, or 6.5 mg BID) in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8 mg/day (4 mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10 mg/day and 13 mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16 weeks. The MTD of RO4987655 for Japanese patients was determined as 8 mg/day (4 mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors.
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21
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Strickland LR, Pal HC, Elmets CA, Afaq F. Targeting drivers of melanoma with synthetic small molecules and phytochemicals. Cancer Lett 2015; 359:20-35. [PMID: 25597784 DOI: 10.1016/j.canlet.2015.01.016] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 01/06/2015] [Accepted: 01/10/2015] [Indexed: 12/19/2022]
Abstract
Melanoma is the least common form of skin cancer, but it is responsible for the majority of skin cancer deaths. Traditional therapeutics and immunomodulatory agents have not shown much efficacy against metastatic melanoma. Agents that target the RAS/RAF/MEK/ERK (MAPK) signaling pathway - the BRAF inhibitors vemurafenib and dabrafenib, and the MEK1/2 inhibitor trametinib - have increased survival in patients with metastatic melanoma. Further, the combination of dabrafenib and trametinib has been shown to be superior to single agent therapy for the treatment of metastatic melanoma. However, resistance to these agents develops rapidly. Studies of additional agents and combinations targeting the MAPK, PI3K/AKT/mTOR (PI3K), c-kit, and other signaling pathways are currently underway. Furthermore, studies of phytochemicals have yielded promising results against proliferation, survival, invasion, and metastasis by targeting signaling pathways with established roles in melanomagenesis. The relatively low toxicities of phytochemicals make their adjuvant use an attractive treatment option. The need for improved efficacy of current melanoma treatments calls for further investigation of each of these strategies. In this review, we will discuss synthetic small molecule inhibitors, combined therapies and current progress in the development of phytochemical therapies.
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Affiliation(s)
- Leah Ray Strickland
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Harish Chandra Pal
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Craig A Elmets
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Farrukh Afaq
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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22
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Role of the ERK1/2 pathway in tumor chemoresistance and tumor therapy. Bioorg Med Chem Lett 2014; 25:192-7. [PMID: 25515559 DOI: 10.1016/j.bmcl.2014.11.076] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 11/14/2014] [Accepted: 11/27/2014] [Indexed: 12/23/2022]
Abstract
Chemotherapy is one of the important methods for treatment in tumors. However, many tumor patients may experience tumor recurrence because of treatment failure due to chemoresistance. Although many signaling pathways could influence chemoresistance of tumor cells, the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway has gained significant attention because of its implications in signaling and which has crosstalk with other signaling pathways. Extensive studies conclude that ERK1/2 pathway is responding to chemoresistance in many kinds of malignant tumors. The aim of this review is to discuss on the role of ERK1/2 pathway in chemoresistance and therapy of tumors. A comprehensive understanding of ERK1/2 pathway in chemoresistance of tumors could provide novel avenues for treatment strategies of tumors.
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23
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Jeong WJ, Cha PH, Choi KY. Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer. World J Gastroenterol 2014; 20:9862-9871. [PMID: 25110417 PMCID: PMC4123368 DOI: 10.3748/wjg.v20.i29.9862] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/14/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Administration of monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer (mCRC). However, the efficacy of these mAbs is limited due to genetic variation among patients, in particular K-ras mutations. The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC. Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF, MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors. Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation, our understanding of their mode of action is limited. Rational drug development based on stringent preclinical data, biomarker validation, and proper selection of patients is of paramount importance in the treatment of mCRC. In this review, we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFR-Ras-ERK and PI3K signalings.
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24
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MEK1/2 inhibitors in the treatment of gynecologic malignancies. Gynecol Oncol 2014; 133:128-37. [DOI: 10.1016/j.ygyno.2014.01.008] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 01/06/2014] [Accepted: 01/08/2014] [Indexed: 12/19/2022]
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Martin-Liberal J, Lagares-Tena L, Larkin J. Prospects for MEK inhibitors for treating cancer. Expert Opin Drug Saf 2014; 13:483-95. [PMID: 24597490 DOI: 10.1517/14740338.2014.892578] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION The MAPK pathway is a signaling network that plays a key role in many normal cellular processes and in a large number of human malignancies. One of its effectors, MEK, is essential for the carcinogenesis of different tumors. In recent years, several drugs able to inhibit MEK have been assessed in clinical trials. Trametinib has recently become the first MEK inhibitor licensed for cancer treatment (advanced melanoma). AREAS COVERED We comprehensively review the safety and clinical efficacy of the family of MEK inhibitors, either alone or in combination with other drugs. We discuss data ranging from the Phase III trial of trametinib in melanoma to the most recent drugs with early signs of antitumor activity. In addition, we explain the reasons for the unsuccessful results of the early trials with MEK inhibitors and provide a view of their role in cancer treatment in forthcoming years. EXPERT OPINION MEK inhibitors are a potentially safe and active treatment option for the treatment of many human malignancies. The information provided by a large series of studies currently ongoing will be very valuable in order to optimize their use. Adequate selection of patients is crucial for achieving successful results with these compounds.
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Affiliation(s)
- Juan Martin-Liberal
- The Royal Marsden Hospital , Fulham Road, London SW3 6JJ , UK +44 20 7811 8576 ; +44 20 7811 8103 ;
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