Preclinical IN VIVO study: BRAFi+MEKi for NRAS mutated tumors in melanoma PDX models

01/10/2018 to 30/04/2019

Patients with NRAS-mutated metastatic melanoma often have an aggressive disease requiring fast-acting, effective therapy. The MEK inhibitor binimetinib shows an overall response rate of 15% in patients with NRAS-mutated melanoma, providing the backbone for combination strategies. Our previous studies have shown that in NRAS-mutated melanoma, the antitumor activity of the MEK inhibitor binimetinib is significantly enhanced by the BRAF inhibitor encorafenib by induction of ER stress, leading to death of melanoma cells by apoptotic mechanisms. BRAFi significantly increased pERK, but also growth inhibition and apoptosis induced by MEKi in monolayers, spheroids, organotypic and patient-derived tissue section cultures of NRAS mutan melanoma. Encorafenib in combination with binimetinib was well tolerated in a Phase III study with strong antitumor activity in BRAF mutant melanoma, allowing rapid evaluation of NRAS mutant melanoma immediately. The in vivo data to be evaluated in this project provide a mechanistic justification for the evaluation of binimetinib in combination with encorafenib in clinical trials in NRAS-mutated metastatic melanoma.