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
Open Access
- 10 September 2014
- journal article
- research article
- Published by Wiley in Molecular Oncology
- Vol. 9 (1), 323-333
- https://doi.org/10.1016/j.molonc.2014.08.015
Abstract
Purpose To investigate the incidence of cMET gene copy number changes and protein overexpression in Chinese gastric cancer (GC) and to preclinically test the hypothesis that the novel, potent and selective cMET small‐molecule inhibitor volitinib, will deliver potent anti‐tumor activity in cMET‐dysregulated GC patient‐derived tumor xenograft (PDX) models. Experimental design A range of assays were used and included; in vitro cell line panel screening and pharmacodynamic (PD) analysis, cMET fluorescence in‐situ hybridization (FISH) and immunohistochemical (IHC) tissue microarray (TMA) analysis of Chinese GC (n = 170), and anti‐tumor efficacy testing and PD analysis of gastric PDX models using volitinib. Results The incidence of cMET gene amplification and protein overexpression within Chinese patient GC tumors was 6% and 13%, respectively. Volitinib displayed a highly selective profile across a gastric cell line panel, potently inhibiting cell growth only in those lines with dysregulated cMET (EC50 values 0.6 nM/L–12.5 nM/L). Volitinib treatment led to pharmacodynamic modulation of cMET signaling and potent tumor stasis in 3/3 cMET‐dysregulated GC PDX models, but had negligible activity in a GC control model. Conclusions 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.Keywords
This publication has 40 references indexed in Scilit:
- Phase II Study Evaluating 2 Dosing Schedules of Oral Foretinib (GSK1363089), cMET/VEGFR2 Inhibitor, in Patients with Metastatic Gastric CancerPLOS ONE, 2013
- MET Amplification Identifies a Small and Aggressive Subgroup of Esophagogastric Adenocarcinoma With Evidence of Responsiveness to CrizotinibJournal of Clinical Oncology, 2011
- Durable Complete Response of Metastatic Gastric Cancer with Anti-Met Therapy Followed by Resistance at RecurrenceCancer Discovery, 2011
- MET Expression and Amplification in Patients with Localized Gastric CancerCancer Epidemiology, Biomarkers & Prevention, 2011
- Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trialThe Lancet, 2010
- Why does Japan have a high incidence of gastric cancer? Comparison of gastritis between UK and Japanese patientsGut, 2006
- The global health burden of infection‐associated cancers in the year 2002International Journal of Cancer, 2006
- Expression of c‐met/HGF Receptor in Human Non‐small Cell Lung Carcinomas in vitro and in vivo and Its Prognostic SignificanceJapanese Journal of Cancer Research, 1996
- Frequent amplification of the c-met gene in scirrhous type stomach cancerBiochemical and Biophysical Research Communications, 1992
- Scatter factor is a fibroblast-derived modulator of epithelial cell mobilityNature, 1987