Volitinib, a potent and highly selective c‐Met inhibitor, effectively blocks c‐Met signaling and growth in c‐MET amplified gastric cancer patient‐derived tumor xenograft models

Abstract

This study provides an assessment of tumor cMET gene copy number changes and protein overexpression incidence in a cohort of Chinese GC patients. To our knowledge, this is the first study to demonstrate anti-tumor efficacy in a panel of cMET-dysregulated gastric cancer PDX models, using a novel selective cMET-inhibitor (volitinib). Thus, the translational science presented here provides strong rationale for the investigation of volitinib as a therapeutic option for patients with GC tumors harboring amplified cMET.

MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer

“…IHC could be considered a practical screening test for MET amplification. In our present study, MET amplification was found in only four patients, in accordance with the protein overexpression profile, which is a similar rate to that reported in a previous publication [32]. Although MET amplification has been described as an unfavorable factor for outcomes in gastric cancer, ovarian cancer, and NSCLC [39], a similar effect on overall survival was not observed in our current cohort, probably due to the small number of amplified patients.…”

“…We examined MET, ROS1, and ALK status in gastric cancer cell lines and compared the effects of crizotinib between a MET-amplified cell line and various cell lines that were negative for this genetic alteration. We confirmed that MKN45 was positive for MET amplification and displayed high sensitivity to the crizotinib-targeted agent in vitro, and that hypersensitivity to crizotinib was predominantly dependent on MET signaling through the inhibition of phospho-MET and the downstream signaling ERK, AKT, and STAT pathways-results that were largely consistent with those of previous reports [24,32,38].…”

“…A higher MET protein overexpression rate (42.9 %) was found in our current analysis compared with other studies in Chinese gastric cancer patients [24,32]. These results are likely a consequence of higher proportion of advanced stage.…”

“…Evidence exists for the role of MET in signaling pathways such as the PI-3-kinase/AKT, Ras/RAF/MEK/ERK, STAT, and FAK pathways, which are associated with cell proliferation, migration, invasion, and angiogenesis [32][33][34]. A number of novel agents targeting the MET/HGF axis have undergone clinical trials in gastric cancer patients, including MET antibodies such as onartuzumab (MetMab) and rilotumumab and small-molecule tyrosine kinase inhibitors such as crizotinib, AMG337, INC280 and volitinib.…”

Targeted Therapy in Advanced Gastric Cancer: An Updated Review

“…The c-MET inhibitor crizotinib was able to induce tumor regression in a PDGCX mouse model [116]. Volitinib, an inhibitor of c-MET, and saracatinib (AZD0530), an inhibitor of c-MET's downstream target Src, also showed antitumor effects in gastric cancer-derived xenograft models [117][118][119]. Onartuzumab, or MetMAb, is a monovalent monoclonal antibody that binds to the MET receptor, thus preventing HGF binding and its downstream signaling.…”