1. ERK Inhibitor LY3214996-Based Treatment Strategies for
- Author
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Jens, Köhler, Yutong, Zhao, Jiaqi, Li, Prafulla C, Gokhale, Hong L, Tiv, Aine R, Knott, Margaret K, Wilkens, Kara M, Soroko, Mika, Lin, Chiara, Ambrogio, Monica, Musteanu, Atsuko, Ogino, Jihyun, Choi, Magda, Bahcall, Arrien A, Bertram, Emily S, Chambers, Cloud P, Paweletz, Shripad V, Bhagwat, Jason R, Manro, Ramon V, Tiu, and Pasi A, Jänne
- Subjects
Genes, ras ,Lung Neoplasms ,Cell Line, Tumor ,Humans ,Oncogenes ,Protein Kinase Inhibitors ,Article - 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 anti-tumor 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.
- Published
- 2020