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|Ref Type||Journal Article|
|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||Molecular cancer therapeutics|
|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.|
|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|