Reference Detail

Ref Type

Journal Article

PMID

(33536188)

Authors

Köhler J, Zhao Y, Li J, Gokhale PC, Tiv HL, Knott AR, Wilkens MK, Soroko KM, Lin M, Ambrogio C, Musteanu M, Ogino A, Choi J, Bahcall M, Bertram AA, Chambers ES, Paweletz CP, Bhagwat SV, Manro JR, Tiu RV, Jänne PA

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	20	4	2021 04	641-654	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS Q61K	lung carcinoma	sensitive	LY3214996	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, patient-derived lung carcinoma cells harboring NRAS Q61K were sensitive to LY3214996 treatment in culture, and LY3214996 treatment led to reduction of tumor growth in a patient-derived xenograft (PDX) model (PMID: 33536188).	33536188
NRAS Q61K	lung carcinoma	sensitive	Abemaciclib + LY3214996	Preclinical - Pdx	Actionable	In a preclinical study, combination treatment with LY3214996 and Verzenio (abemaciclib) led to additive effects on tumor growth inhibition in a patient-derived xenograft (PDX) model of lung carcinoma harboring NRAS Q61K (PMID: 33536188).	33536188