Reference Detail

Ref Type

Journal Article

PMID

(31227518)

Authors

Gao Y, Maria A, Na N, da Cruz Paula A, Gorelick AN, Hechtman JF, Carson J, Lefkowitz RA, Weigelt B, Taylor BS, Zhao H, Reis-Filho JS, de Stanchina E, Rosen N, Yao Z, Yaeger R

Title

V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	9	9	2019 Sep	1182-1191	Cancer Discov

URL

Abstract Text

We report the emergence of the novel MEK1V211D gatekeeper mutation in a patient with BRAFK601E colon cancer treated with the allosteric MEK inhibitor binimetinib and the anti-EGFR antibody panitumumab. The MEK1V211D mutation concurrently occurs in the same cell with BRAFK601E and leads to RAF-independent activity but remains regulated by RAF. The V211D mutation causes resistance to binimetinib by both increasing the catalytic activity of MEK1 and reducing its affinity for the drug. Moreover, the mutant exhibits reduced sensitivity to all the allosteric MEK inhibitors tested. Thus, this mutation serves as a general resistance mutation for current MEK inhibitors; however, it is sensitive to a newly reported ATP-competitive MEK inhibitor, which therefore could be used to overcome drug resistance. SIGNIFICANCE: We report a resistance mechanism to allosteric MEK inhibitors in the clinic. A MEK1V211D mutation developed in a patient with BRAFK601E colon cancer on MEK and EGFR inhibitors. This mutant increases the catalytic activity of MEK1 and reduces its affinity for binimetinib, but remains sensitive to ATP-competitive MEK inhibitors.This article is highlighted in the In This Issue feature, p. 1143.

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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	V211D	missense	gain of function	MAP2K1 V211D lies within the protein kinase domain of the Map2k1 protein (UniProt.org). V211D confers a gain of function to Map2k1, as demonstrated by increased phosphorylation of Mek and Erk in cultured cells and in vitro kinase assays, and also demonstrates Braf and Mek inhibitor resistance (PMID: 29753091, PMID: 19915144, PMID: 31227518).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF K601E MAP2K1 V211D	colon cancer	resistant	Binimetinib	Preclinical - Pdx	Actionable	In a preclinical study, Mektovi (binimetinib) did not inhibit Rsk and Erk phosphorylation, and had no effect on tumor growth in patient-derived xenograft (PDX) models of metastatic colon cancer harboring BRAF K601E and MAP2K1 V211D (PMID: 31227518).	31227518
MAP2K1 V211D	Advanced Solid Tumor	predicted - resistant	Cobimetinib	Preclinical - Biochemical	Actionable	In a preclinical study, Cotellic (cobimetinib) did not inhibit kinase activity of MAP2K1 V211D in an in vitro assay (PMID: 31227518).	31227518
MAP2K1 V211D	Advanced Solid Tumor	predicted - resistant	Binimetinib	Preclinical - Biochemical	Actionable	In a preclinical study, Mektovi (binimetinib) did not inhibit kinase activity of MAP2K1 V211D in an in vitro assay (PMID: 31227518).	31227518
BRAF K601E MAP2K1 V211D	colon cancer	sensitive	MAP855	Preclinical - Pdx	Actionable	In a preclinical study, MAP855 inhibited Rsk and Erk phosphorylation, and resulted in 30% tumor regression in patient-derived xenograft (PDX) models of metastatic colon cancer harboring BRAF K601E and MAP2K1 V211D (PMID: 31227518).	31227518
BRAF K601E MAP2K1 V211D	colon cancer	predicted - resistant	Binimetinib + Panitumumab	Case Reports/Case Series	Actionable	In a clinical case study, a patient with metastatic colon cancer harboring BRAF K601E developed progressive disease after 6 weeks of Mektovi (binimetinib) and Vectibix (panitumumab) combination treatment, MAP2K1 V211D was identified as a co-occuring mutation in the biopsy from the new metastasis site (PMID: 31227518).	31227518
BRAF K601E MAP2K1 V211D	colon cancer	resistant	Binimetinib + Cetuximab	Preclinical - Pdx	Actionable	In a preclinical study, Mektovi (binimetinib) and Erbitux (cetuximab) combination did not inhibit Rsk and Erk phosphorylation, and had no effect on tumor growth in patient-derived xenograft (PDX) models of metastatic colon cancer harboring BRAF K601E and MAP2K1 V211D (PMID: 31227518).	31227518