ERK Inhibitor LY3214996-Based Treatment Strategies forRAS-Driven Lung Cancer
Open Access
- 3 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 20 (4), 641-654
- https://doi.org/10.1158/1535-7163.mct-20-0531
Abstract
RAS gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them the MAPK, PI3K, and RB pathways. Within the MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals and activating cytoplasmic and nuclear targets. In view of disappointing antitumor activity and toxicity of continuously applied MEK inhibitors in patients with KRAS-mutant lung cancer, research has recently focused on ERK1/2 proteins as therapeutic targets and on ERK inhibitors for their ability to prevent bypass and feedback pathway activation. Here, we show that intermittent application of the novel and selective ATP-competitive ERK1/2 inhibitor LY3214996 exerts single-agent activity in patient-derived xenograft (PDX) models of RAS-mutant lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and—equally important—to identify biomarkers for patient stratification.Keywords
Funding Information
- Eli Lilly & Company
- NCI (R35CA220497)
- German Cancer Aid foundation (70111755)
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