Reference Detail

Ref Type

Journal Article

PMID

(26582713)

Authors

Gannon HS, Kaplan N, Tsherniak A, Vazquez F, Weir BA, Hahn WC, Meyerson M

Title

Identification of an "Exceptional Responder" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted Therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer research : MCR	14	2	2016 Feb	207-15	Mol Cancer Res

URL

Abstract Text

The identification of somatic genetic alterations that confer sensitivity to pharmacologic inhibitors has led to new cancer therapies. To identify mutations that confer an exceptional dependency, shRNA-based loss-of-function data were analyzed from a dataset of numerous cell lines to reveal genes that are essential in a small subset of cancer cell lines. Once these cell lines were determined, detailed genomic characterization from these cell lines was utilized to ascertain the genomic aberrations that led to this extreme dependency. This method, in a large subset of lung cancer cell lines, yielded a single lung adenocarcinoma cell line, NCI-H1437, which is sensitive to RNA interference of MAP2K1 expression. Notably, NCI-H1437 is the only lung cancer cell line included in the dataset with a known activating mutation in MAP2K1 (Q56P). Subsequent validation using shRNA and CRISPR-Cas9 confirmed MAP2K1 dependency. In vitro and in vivo inhibitor studies established that NCI-H1437 cells are sensitive to MEK1 inhibitors, including the FDA-approved drug trametinib. Like NCI-H1437 cells, the MAP2K1-mutant cell lines SNU-C1 (colon) and OCUM-1 (gastric) showed decreased viability after MAP2K1 depletion via Cas9-mediated gene editing. Similarly, these cell lines were particularly sensitive to trametinib treatment compared with control cell lines. On the basis of these data, cancers that harbor driver mutations in MAP2K1 could benefit from treatment with MEK1 inhibitors. Furthermore, this functional data mining approach provides a general method to experimentally test genomic features that confer dependence in tumors.Cancers with an activated RAS/MAPK pathway driven by oncogenic MAP2K1 mutations may be particularly sensitive to MEK1 inhibitor treatments.

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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
MAP2K1 Q56P	lung adenocarcinoma	sensitive	Refametinib	Preclinical	Actionable	In a preclinical study, a lung adenocarcinoma cell line harboring MAP2K1 Q56P demonstrated sensitivity to Refametinib (BAY86-9766), resulting in decreased cell viability (PMID: 26582713).	26582713
MAP2K1 Q56P	lung adenocarcinoma	sensitive	PD-0325901	Preclinical	Actionable	In a preclinical study, a lung adenocarcinoma cell line harboring MAP2K1 Q56P demonstrated sensitivity to PD-0325901, resulting in decreased cell viability (PMID: 26582713).	26582713
MAP2K1 F53L	colorectal cancer	sensitive	Trametinib	Preclinical	Actionable	In a preclinical study, a colorectal cancer cell line harboring MAP2K1 F53L demonstrated sensitivity to Mekinist (trametinib) in culture, resulting in decreased cell viability (PMID: 26582713).	26582713
MAP2K1 Q56P	lung adenocarcinoma	sensitive	Selumetinib	Preclinical	Actionable	In a preclinical study, a lung adenocarcinoma cell line harboring MAP2K1 Q56P demonstrated sensitivity to Selumetinib (AZD6244), resulting in decreased cell viability (PMID: 26582713).	26582713
MAP2K1 Q56P	lung adenocarcinoma	sensitive	Trametinib	Preclinical	Actionable	In a preclinical study, a lung adenocarcinoma cell line harboring MAP2K1 Q56P demonstrated sensitivity to Mekinist (trametinib), resulting in decreased cell viability (PMID: 26582713).	26582713
MAP2K1 Q56P	stomach cancer	sensitive	Trametinib	Preclinical	Actionable	In a preclinical study, a gastric cancer cell line harboring MAP2K1 Q56P demonstrated sensitivity to Mekinist (trametinib), resulting in decreased cell viability (PMID: 26582713).	26582713