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Ref Type Journal Article
PMID (28655712)
Authors Emery CM, Monaco KA, Wang P, Balak M, Freeman A, Meltzer J, Delach SM, Rakiec D, Ruddy DA, Korn JM, Haling J, Acker MG, Caponigro G
Title BRAF-inhibitor Associated MEK Mutations Increase RAF-Dependent and -Independent Enzymatic Activity.
Journal Molecular cancer research : MCR
Vol 15
Issue 10
Date 2017 Oct
URL
Abstract Text Alterations in MEK1/2 occur in cancers, both in the treatment-naïve state and following targeted therapies, most notably BRAF and MEK inhibitors in BRAF-V600E-mutant melanoma and colorectal cancer. Efforts were undertaken to understand the effects of these mutations, based upon protein structural location, and MEK1/2 activity. Two categories of MEK1/2 alterations were evaluated, those associated with either the allosteric pocket or helix-A. Clinically, MEK1/2 alterations of the allosteric pocket are rare and we demonstrate that they confer resistance to MEK inhibitors, while retaining sensitivity to BRAF inhibition. Most mutations described in patients fall within, or are associated with, helix-A. Mutations in this region reduce sensitivity to both BRAF and MEK inhibition and display elevated phospho-ERK1/2 levels, independent from increases in phospho-MEK1/2. Biochemical experiments with a representative helix-A variant, MEK1-Q56P, reveal both increased catalytic efficiency of the activated enzyme, and phosphorylation-independent activity relative to wild-type MEK1. Consistent with these findings, MEK1/2 alterations in helix A retain sensitivity to downstream antagonism via pharmacologic inhibition of ERK1/2. This work highlights the importance of classifying mutations based on structural and phenotypic consequences, both in terms of pathway signaling output and response to pharmacologic inhibition.Implications: This study suggests that alternate modes of target inhibition, such as ERK inhibition, will be required to effectively treat tumors harboring these MEK1/2-resistant alleles. Mol Cancer Res; 15(10); 1431-44. ©2017 AACR.

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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 I111N missense gain of function - predicted MAP2K1 I111N lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I111N is predicted to confer a gain of function to the Map2k1 protein as demonstrated by increased Mek and Erk phosphorylation in cultured cells (PMID: 19915144), and is also associated with resistance to Mek inhibitors (PMID: 19915144, PMID: 28655712). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E MAP2K1 V211D melanoma sensitive Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) inhibited proliferation of melanoma cells harboring BRAF V600E and expressing MAP2K1 V211D in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 Q56P melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 Q56P demonstrated resistance to treatment with Zelboraf (vemurafenib) in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 Q56P melanoma sensitive Ulixertinib Preclinical - Cell culture Actionable In a preclinical study, BVD-523 (ulixertinib) inhibited proliferation of melanoma cells harboring BRAF V600E and expressing MAP2K1 Q56P in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 P124L melanoma decreased response Trametinib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 P124L demonstrated a decreased response to treatment with Mekinist (trametinib) in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 I111N melanoma sensitive Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) inhibited proliferation of melanoma cells harboring BRAF V600E and expressing MAP2K1 I111N in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 V211D melanoma sensitive Ulixertinib Preclinical - Cell culture Actionable In a preclinical study, BVD-523 (Ulixertinib) inhibited proliferation of melanoma cells harboring BRAF V600E and expressing MAP2K1 V211D in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 E203K melanoma sensitive Ulixertinib Preclinical - Cell culture Actionable In a preclinical study, BVD-523 (ulixertinib) inhibited proliferation of melanoma cells harboring BRAF V600E and expressing MAP2K1 E203K in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 C121S melanoma resistant Trametinib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 C121S demonstrated resistance to treatment with Mekinist (trametinib) in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 L115P melanoma conflicting Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) inhibited proliferation of melanoma cells harboring BRAF V600E and expressing MAP2K1 L115P in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 L115P melanoma conflicting Trametinib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 L115P demonstrated resistance to treatment with Mekinist (trametinib) in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 E203K melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 E203K demonstrated resistance to treatment with Zelboraf (vemurafenib) in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 V211D melanoma resistant Trametinib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 V211D demonstrated resistance to treatment with Mekinist (trametinib) in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 E203K melanoma conflicting Trametinib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 E203K demonstrated resistance to treatment with Mekinist (trametinib) in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 P124L melanoma decreased response Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 P124L demonstrated a decreased response to treatment with Zelboraf (vemurafenib) in culture (PMID: 28655712). 28655712
BRAF V600E MAP2K1 I111N melanoma resistant Trametinib Preclinical - Cell culture Actionable In a preclinical study, melanoma cells harboring BRAF V600E and expressing MAP2K1 I111N demonstrated resistance to treatment with Mekinist (trametinib) in culture (PMID: 28655712). 28655712