RT Journal Article
SR Electronic
T1 ERK Inhibitor LY3214996-Based Treatment Strategies for <em>RAS</em>-Driven Lung Cancer
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 641
OP 654
DO 10.1158/1535-7163.MCT-20-0531
VO 20
IS 4
A1 Köhler, Jens
A1 Zhao, Yutong
A1 Li, Jiaqi
A1 Gokhale, Prafulla C.
A1 Tiv, Hong L.
A1 Knott, Aine R.
A1 Wilkens, Margaret K.
A1 Soroko, Kara M.
A1 Lin, Mika
A1 Ambrogio, Chiara
A1 Musteanu, Monica
A1 Ogino, Atsuko
A1 Choi, Jihyun
A1 Bahcall, Magda
A1 Bertram, Arrien A.
A1 Chambers, Emily S.
A1 Paweletz, Cloud P.
A1 Bhagwat, Shripad V.
A1 Manro, Jason R.
A1 Tiu, Ramon V.
A1 Jänne, Pasi A.
YR 2021
UL http://mct.aacrjournals.org/content/20/4/641.abstract
AB 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.This article is featured in Highlights of This Issue, p. 623