A way to overcome resistance to FGFR therapy in cholangiocarcinoma

A combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma is proposed by a study published in Cancer Discovery, showing that EGFR inhibition potentiates FGFR inhibitor therapy in these patients.

Nearly 20% of intrahepatic cholangiocarcinomas exhibit chromosomal fusions, point mutations, or in-frame deletions of FGFR2; multiple selective FGFR inhibitors have shown efficacy in these settings. Therefore FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions, but the response rate is moderate and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. After a thorough analysis using patient-derived models of FGFR2 fusion–positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies, authors found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild- type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. «An urgent need still exists to improve the effectiveness of FGFR-targeted therapy, mitigate toxicity and identify additional treatment options for FGFR inhibitors resistant disease», authors say. «Rebound activation of MEK/ERK signaling protects against cell death and maintains proliferation in response to FGFR inhibition across a series of FGFR2+  intrahepatic cholangiocarcinoma models. The feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion– positive cholangiocarcinoma: therefore these data support the use of EGFR inhibitors to potentiate FGFR inhibitors efficacy in the treatment-naïve setting and to overcome adaptive resistance».