Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer research : MCR	15	10	2017 Oct	1431-1444	Mol Cancer Res

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 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 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 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 Q56P	melanoma	sensitive	Ulixertinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ulixertinib (BVD-523) inhibited proliferation of melanoma cells harboring BRAF V600E and expressing MAP2K1 Q56P 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 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
BRAF V600E MAP2K1 V211D	melanoma	sensitive	Ulixertinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ulixertinib (BVD-523) inhibited proliferation of melanoma cells harboring BRAF V600E and expressing MAP2K1 V211D 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 P124L	melanoma	predicted - resistant	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 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 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 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 C121S	melanoma	conflicting	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 E203K	melanoma	conflicting	Ulixertinib	Preclinical - Cell culture	Actionable	In a preclinical study, Ulixertinib (BVD-523) inhibited proliferation of melanoma cells harboring BRAF V600E and expressing MAP2K1 E203K in culture (PMID: 28655712).	28655712