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Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance

Authors
 Magda Bahcall  ;  Cloud P Paweletz  ;  Yanan Kuang  ;  Luke J Taus  ;  Taebo Sim  ;  Nam Doo Kim  ;  Kshiti H Dholakia  ;  Christie J Lau  ;  Prafulla C Gokhale  ;  Pratik R Chopade  ;  Fangxin Hong  ;  Zihan Wei  ;  Jens Köhler  ;  Paul T Kirschmeier  ;  Jiannan Guo  ;  Sujuan Guo  ;  Stephen Wang  ;  Pasi A Jänne 
Citation
 MOLECULAR CANCER THERAPEUTICS, Vol.21(2) : 322-335, 2022-02 
Journal Title
MOLECULAR CANCER THERAPEUTICS
ISSN
 1535-7163 
Issue Date
2022-02
MeSH
Animals ; Drug Resistance, Neoplasm / drug effects* ; Female ; High-Throughput Nucleotide Sequencing / methods* ; Humans ; Mice ; Molecular Docking Simulation / methods* ; Protein Kinase Inhibitors / pharmacology ; Protein Kinase Inhibitors / therapeutic use*
Abstract
MET-targeted therapies are clinically effective in MET-amplified and MET exon 14 deletion mutant (METex14) non-small cell lung cancers (NSCLCs), but their efficacy is limited by the development of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs) (type I/II) have been developed or are under clinical evaluation, which may overcome MET-mediated drug resistance mechanisms. In this study, we assess secondary MET mutations likely to emerge in response to treatment with single-agent or combinations of type I/type II MET TKIs using TPR-MET transformed Ba/F3 cell mutagenesis assays. We found that these inhibitors gave rise to distinct secondary MET mutant profiles. However, a combination of type I/II TKI inhibitors (capmatinib and merestinib) yielded no resistant clones in vitro The combination of capmatinib/merestinib was evaluated in vivo and led to a significant reduction in tumor outgrowth compared with either MET inhibitor alone. Our findings demonstrate in vitro and in vivo that a simultaneous treatment with a type I and type II MET TKI may be a clinically viable approach to delay and/or diminish the emergence of on target MET-mediated drug-resistance mutations.
Full Text
https://aacrjournals.org/mct/article/21/2/322/678522/Combination-of-Type-I-and-Type-II-MET-Tyrosine
DOI
10.1158/1535-7163.MCT-21-0344
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Sim, Taebo(심태보)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188552
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