Rapid resistance of FGFR-driven gastric cancers to regorafenib and targeted FGFR inhibitors can be overcome by parallel inhibition of MEK.

Abstract

Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers (GC). Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced GC. There are currently no biomarkers which predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 GC cell lines, we identified 5 GC lines which were exquisitely sensitive to regorafenib, 4 of which harboured amplification or overexpression of FGFR family members. These 4 lines were also sensitive to the FGFR-specific inhibitors BGJ398, erdafitinib and TAS-120. Regorafenib inhibited FGFR-driven MAPK signaling in these cell lines, and knockdown studies confirmed their dependence on specific FGFRs for proliferation. In the INTEGRATE trial cohort, amplification or overexpression of FGFR's 1-4 was detected in 8-19% of cases, however this was not associated with improved progression free or survival and no objective responses were observed in these cases. Further pre-clinical analyses revealed FGFR-driven GC lines rapidly reactivate MAPK/ERK signaling in response to FGFR inhibition, which may underlie the limited clinical response. Importantly, combination treatment with FGFR inhibitors and the MEK inhibitor trametinib delayed MAPK/ERK reactivation and synergistically inhibited proliferation of FGFR-driven GC cell lines. These findings suggest that up-front combinatorial inhibition of FGFR and MEK may represent a more effective treatment strategy for these tumours.