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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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	26	12	2020 Jun 15	2932-2945	Clin Cancer Res

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
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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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

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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	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	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	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	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
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	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

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