Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors

Abstract

Many small molecule inhibitors of the cMET receptor tyrosine kinase have been evaluated in clinical trials for the treatment of cancer and resistance-conferring mutations of cMET are beginning to be reported for a number of such compounds. There is now a need to understand specific cMET mutations at the molecular level, particularly concerning small molecule recognition. Toward this end, we report here the first crystal structures of the recent clinically observed resistance-conferring D1228V cMET mutant in complex with small molecule inhibitors, along with a crystal structure of wild-type cMET bound by the clinical compound savolitinib and supporting cellular, biochemical, and biophysical data. Our findings indicate that the D1228V alteration induces conformational changes in the kinase, which could have implications for small molecule inhibitor design. The data we report here increases our molecular understanding of the D1228V cMET mutation and provides insight for future inhibitor design.

SHP2 Inhibition Influences Therapeutic Response to Tepotinib in Tumors with MET Alterations

“…Mechanisms of resistance to MET TKIs are heterogeneous and may also differ based on the class of MET TKI (type I or II) ( Backes et al., 2008 ; Gherardi et al., 2012 ; Recondo et al., 2020 ). For instance, secondary MET kinase domain mutations such as D1228V, or high-level MET amplification, have been described as mechanisms of resistance to MET TKIs ( Collie et al., 2019 ; Recondo et al., 2020 ), and sequential treatment with a structurally different MET TKI was found to be effective in overcoming resistance in these settings ( Recondo et al., 2020 ). Guo et al.…”

Early prediction of resistance to tyrosine kinase inhibitors by plasma monitoring of EGFR mutations in NSCLC: a new algorithm for patient selection and personalized treatment

“…A number of trials have been activated to treat patients with double or multiple mutations with combined treatments. For instance, tumors carrying EGFR mutations and met amplification can be efficiently treated with osimertinib plus savolitinib [24][25][26].…”

Comprehensive review of targeted therapy for colorectal cancer

“…AMG 337, an oral ATP-competitive TKI specific to MET, caused a strong response in patients with MET-amplified upper gastrointestinal tract cancer in phase I and II trials. 325,326 Savolitinib, a selective MET inhibitor, displayed marked antitumour potential under experimental conditions and appeared to be effective against renal cell cancer 327,328 and is being investigated in a metastatic CRC phase I trial. Capmatinib, another selective MET inhibitor, has been demonstrated as a good supplementary agent to gefitinib in patients with EGFR-mutant, MET-amplified NSCLC.…”