ERK Inhibitor LY3214996-Based Treatment Strategies for RAS-Driven Lung Cancer.

摘要: RAS gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them MAPK, PI3K, and RB pathways. Within MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals activating cytoplasmic nuclear targets. In view of disappointing antitumor activity toxicity continuously applied MEK inhibitors patients with KRAS-mutant cancer, research has recently focused on as therapeutic targets ERK their ability to prevent bypass feedback pathway activation. Here, we show that intermittent application novel selective ATP-competitive inhibitor LY3214996 exerts single-agent patient-derived xenograft (PDX) models RAS-mutant Combination treatments were well tolerated resulted synergistic (ERKi plus PI3K/mTORi LY3023414) additive CDK4/6i abemaciclib) tumor growth inhibition PDX models. Future clinical trials required investigate if inhibitor-based treatment schedules can overcome toxicities observed continuous and-equally important-to identify biomarkers patient stratification.