Article
Chemistry, Medicinal
Chaofan Wang, Jie Li, Lingzhi Qu, Xia Tang, Xiaojuan Song, Fang Yang, Xiaojuan Chen, Qianmeng Lin, Weibin Lin, Yang Zhou, ZhengChao Tu, Yongheng Chen, Zhang Zhang, Xiaoyun Lu
Summary: MET alterations are crucial in NSCLC and gastric cancers. We designed and optimized a series of new c-Met inhibitors using molecular hybridization and macrocyclization strategy, among which D6808 exhibited potent inhibitory activity, extraordinary target specificity, and promise for further anticancer drug development.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Xiuning Le, Lingzhi Hong, Chuck Hensel, Rongrong Chen, Haley Kemp, Niamh Coleman, Christine A. Ciunci, Stephen Liu, Marcelo Negrao, Jennifer Yen, Xuefeng Xia, Juergen Scheuenpflug, Christopher Stroh, Dilafruz Juraeva, Anne Tsao, David Hong, Victoria Raymond, Paul Paik, Jianjun Zhang, John Heymach
Summary: METex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether METex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.
JCO PRECISION ONCOLOGY
(2021)
Article
Oncology
Jonathan M. Tsai, Aaron N. Hata, Jochen K. Lennerz
Summary: Comprehensive genetic profiling using next-generation sequencing is crucial in precision oncology, where accurate variant annotation plays a key role. This article highlights inconsistencies in variant annotation for the MET D1228N exon 19 resistance mutations, emphasizing the importance of avoiding erroneous interpretation when annotated on different transcripts.
Article
Oncology
Yu-Ra Choi, Eun Hye Kang, Sunshin Kim, Seog-Yun Park, Ji-Youn Han, Youngjoo Lee
Summary: This study evaluated the efficacy of single MET inhibition in EGFR-mutant and MET-amplified lung cancer and found that it produced a short-lived response. Further research on novel combination therapy schedules is needed to achieve long-lasting efficacy with less toxicity.
BRITISH JOURNAL OF CANCER
(2023)
Article
Pharmacology & Pharmacy
Zhen Chen, Karin A. Vallega, Haiying Chen, Jia Zhou, Suresh S. Ramalingam, Shi-Yong Sun
Summary: The natural product berberine, used in traditional Chinese medicine, has been shown to synergize with the first third-generation EGFR-tyrosine kinase inhibitor osimertinib to selectively decrease survival of MET-amplified osimertinib-resistant NSCLC cell lines through induction of apoptosis. This combination was also effective in suppressing the growth of MET-amplified osimertinib-resistant xenografts in nude mice and well tolerated, showing potential efficacy in overcoming osimertinib acquired resistance caused by MET amplification.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Oncology
Jiangping Yang, Ping Zhou, Min Yu, Yan Zhang
Summary: This case study reported a patient with ROS1-rearranged non-small cell lung cancer who developed MET amplification resistance after treatment with ROS1-tyrosine kinase inhibitors. The findings suggest that MET amplification may be a novel mechanism for developing resistance to ROS1-TKIs and warrants further investigation into combination treatments with highly potent and selective MET-TKIs.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
James P. Solomon, Soo-Ryum Yang, Noura J. Choudhury, Ryan N. Ptashkin, Nasrin Eslamdoost, Christina J. Falcon, Axel Martin, Andrew Plodkowski, Clare Wilhelm, Ronglai Shen, Marc Ladanyi, Michael Berger, Yanming Zhang, Alexander Drilon, Maria E. Arcila
Summary: This study validated and optimized the utility of next-generation sequencing (NGS) in assessing MET copy number alterations, achieving high concordance, sensitivity, and specificity. MET copy gains and amplifications were found in certain malignancies, with high-level/focal amplification associated with targeted therapy response.
CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Ryan J. Hartmaier, Aleksandra A. Markovets, Myung Ju Ahn, Lecia Sequist, Ji-Youn Han, Byoung Chul Cho, Helena A. Yu, Sang-We Kim, James Chih-Hsin Yang, Jong-Seok Lee, Wu-Chou Su, Dariusz M. Kowalski, Sergey Orlov, Song Ren, Paul Frewer, Xiaoling Ou, Darren A. E. Cross, Nisha Kurian, Mireille Cantarini, Pasi A. Jaenne
Summary: Combining MET inhibitor and EGFR tyrosine kinase inhibitor can overcome acquired osimertinib resistance mediated by MET. In this study, savolitinib and osimertinib combination therapy showed promising results in advanced non-small cell lung cancer patients with MET amplification and EGFR mutation who had progressed on prior EGFR-TKI treatment. The combination therapy demonstrated acceptable safety profile and improved antitumor activity.
Article
Oncology
Jessica K. Lee, Russell Madison, Anthony Classon, Ole Gjoerup, Mark Rosenzweig, Garrett M. Frampton, Brian M. Alexander, Geoffrey R. Oxnard, Jeffrey M. Venstrom, Mark M. Awad, Alexa B. Schrock
Summary: METex14 skipping alterations are oncogenic drivers in a subset of NSCLC patients, comprising 2%-3% of cases. Tissue and liquid samples show high concordance in mutation profiles, indicating potential for predicting responses to MET inhibitors and combination strategies.
JCO PRECISION ONCOLOGY
(2021)
Article
Cell Biology
Pinar Ozden Eser, Raymond M. Paranal, Jieun Son, Elena Ivanova, Yanan Kuang, Heidi M. Haikala, Ciric To, Jeffrey J. Okoro, Kshiti H. Dholakia, Jihyun Choi, Yoonji Eum, Atsuko Ogino, Pavlos Missios, Dalia Ercan, Man Xu, Michael J. Poitras, Stephen Wang, Kenneth Ngo, Michael Dills, Masahiko Yanagita, Timothy Lopez, Mika Lin, Jeanelle Tsai, Nicolas Floch, Emily S. Chambers, Jennifer Heng, Rana Anjum, Alison D. Santucci, Kesi Michael, Alwin G. Schuller, Darren Cross, Paul D. Smith, Geoffrey R. Oxnard, David A. Barbie, Lynette M. Sholl, Magda Bahcall, Sangeetha Palakurthi, Prafulla C. Gokhale, Cloud P. Paweletz, George Q. Daley, Pasi A. Janne
Summary: Some EGFR-mutant, MET-amplified lung cancers may develop dependence on MET activation alone, suggesting that these patients could be treated with a single-agent MET TKI instead of the current standard-of-care EGFR and MET inhibitor combination regimens.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Oncology
Shinichiro Suzuki, Kimio Yonesaka, Takeshi Teramura, Toshiyuki Takehara, Ryoji Kato, Hitomi Sakai, Koji Haratani, Junko Tanizaki, Hisato Kawakami, Hidetoshi Hayashi, Kazuko Sakai, Kazuto Nishio, Kazuhiko Nakagawa
Summary: The study identified MET amplification as a mechanism of resistance to KRAS(G12C) inhibitors in NSCLC. Using MET inhibitor Crizotinib restored sensitivity to sotorasib, and dual inhibition of MET and KRAS(G12C) led to tumor shrinkage in sotorasib-resistant xenograft mice.
CLINICAL CANCER RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Tianyao Lei, Tianwei Xu, Niu Zhang, Xiaoteng Zou, Ziyue Kong, Chenchen Wei, Zhaoxia Wang
Summary: Favorable clinical evidence suggests that combination therapies could improve the efficacy of treatments for advanced non-small cell lung cancer (NSCLC). However, resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) limits the effectiveness of treatments for patients with EGFR-activating mutants. This study discovered that combining osimertinib and anlotinib restored sensitivity to osimertinib in osimertinib-resistant NSCLC cell lines and xenografts, potentially reversing osimertinib resistance.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Oncology
Balazs Jori, Christine Voessing, Judith Pirngruber, Eva Maria Willing, Kathrin Arndt, Markus Falk, Markus Tiemann, Lukas C. Heukamp, Petra Hoffknecht
Summary: This study reports a case of EGFR-mutant lung adenocarcinoma patient who developed acquired resistance through MET amplification and point mutations in MET during treatment with osimertinib, and achieved successful response through sequential treatment.
Article
Medicine, General & Internal
Mingsheng Liu
Summary: This case report suggests that combinational therapy with trastuzumab and crizotinib may be effective in metastatic gastric cancer patients with poor performance status and Her-2 and c-MET amplification. The treatment led to significant alleviation of symptoms and reduction of metastatic manifestations, without observed adverse reactions. Gene sequencing could be valuable, especially in patients with limited treatment options.
Article
Oncology
Caroline E. McCoach, Aiming Yu, David R. Gandara, Jonathan W. Riess, Daniel P. Vang, Tiahong Li, Primo N. Lara, Matthew Gubens, Frances Lara, Philip C. Mack, Laurel A. Beckett, Karen Kelly
Summary: This study aimed to evaluate the safety and preliminary efficacy of the combination of capmatinib and erlotinib in MET-positive non-small-cell lung cancer patients. The recommended phase II dose (RP2D) of the combination was determined to be 400 mg twice daily of capmatinib with 150 mg daily of erlotinib, with an overall response rate (ORR) of 50% and a disease control rate of 50% in patients with EGFR mutant tumors.
JCO PRECISION ONCOLOGY
(2021)