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Ref Type Journal Article
PMID (32122926)
Authors Sato H, Schoenfeld AJ, Siau E, Lu YC, Tai H, Suzawa K, Kubota D, Lui AJW, Qeriqi B, Mattar M, Offin M, Sakaguchi M, Toyooka S, Drilon A, Rosen NX, Kris MG, Solit D, De Stanchina E, Davare MA, Riely GJ, Ladanyi M, Somwar R
Title MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 26
Issue 12
Date 2020 Jun 15
URL
Abstract Text ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes.ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines.Eight of the 75 patients with a ROS1 fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling with minimal effects on AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1 TKIs, and 2 patients harbored NF1 loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of NF1 in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del.We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.

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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
MAP2K1 E41_L54del deletion gain of function MAP2K1 E41_L54del results in the deletion of 14 amino acids in the Map2k1 protein from amino acids 41 to 54 (UniProt.org). E41_L54del results in increased Map2k1 nuclear localization, elevated Erk phosphorylation, and cell transformation in culture, and promotes tumorigenesis and confers resistance to ROS1 tyrosine kinase inhibitors in the context of a ROS1 fusion (PMID: 32122926). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 E41_L54del Advanced Solid Tumor no benefit LY3009120 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing MAP2K1 E41_L54del were not sensitive to LY3009120 in culture (PMID: 32122926). 32122926
MAP2K1 E41_L54del lung cancer sensitive Cobimetinib Preclinical - Cell culture Actionable In a preclinical study, Cotellic (cobimetinib) inhibited growth of transformed human lung cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). 32122926
MAP2K1 E41_L54del lung cancer no benefit LY3009120 Preclinical - Cell culture Actionable In a preclinical study, transformed human lung cells expressing MAP2K1 E41_L54del were not sensitive to LY3009120 in culture (PMID: 32122926). 32122926
MAP2K1 E41_L54del Advanced Solid Tumor sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of transformed cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). 32122926
MAP2K1 E41_L54del lung cancer sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) inhibited growth of transformed human lung cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). 32122926
MAP2K1 E41_L54del lung cancer sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of transformed human lung cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). 32122926
MAP2K1 E41_L54del Advanced Solid Tumor sensitive Cobimetinib Preclinical - Cell culture Actionable In a preclinical study, Cotellic (cobimetinib) inhibited growth of transformed cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). 32122926
MAP2K1 E41_L54del Advanced Solid Tumor sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) inhibited growth of transformed cells expressing MAP2K1 E41_L54del in culture (PMID: 32122926). 32122926