Reference Detail

Ref Type

Journal Article

PMID

(25370473)

Authors

Carlino MS, Fung C, Shahheydari H, Todd JR, Boyd SC, Irvine M, Nagrial AM, Scolyer RA, Kefford RF, Long GV, Rizos H

Title

Preexisting MEK1P124 mutations diminish response to BRAF inhibitors in metastatic melanoma patients.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	21	1	2015 Jan 01	98-105	Clin Cancer Res

URL

Abstract Text

MEK1 mutations in melanoma can confer resistance to BRAF inhibitors, although preexisting MEK1(P124) mutations do not preclude clinical responses. We sought to determine whether recurrent, preexisting MEK1(P124) mutations affected clinical outcome in BRAF inhibitor-treated patients with melanoma.Data from four published datasets were analyzed to determine whether preexisting MEK1(P124) mutations affect radiologic response or progression-free survival (PFS) in patients with BRAF(V600)-mutant metastatic melanoma treated with vemurafenib or dabrafenib. The effects of MEK1(P124) mutations on MAPK pathway activity and response to BRAF inhibition were also investigated in a series of cell models.In a pooled analysis of 123 patients, the presence of a pretreatment MEK1(P124) mutation (N = 12, 10%) was associated with a poorer RECIST response (33% vs. 72% in MEK1(P124Q/S) vs. MEK1(P124) wild-type, P = 0.018), and a shorter PFS (median 3.1 vs. 4.8 months, P = 0.004). Furthermore, MEK1(P124Q/S) mutations were shown to have independent kinase activity and introduction of these mutations into a BRAF-mutant melanoma cell line diminished inhibition of ERK phosphorylation by dabrafenib and enhanced clonogenic survival in the presence of dabrafenib compared with cells ectopically expressing wild-type MEK1. Consistent with these data, two BRAF-mutant cell lines with endogenous MEK1(P124) mutations showed intermediate sensitivity to dabrafenib, but were highly sensitive to downstream inhibition of MEK or ERK.Taken together, our data indicate that preexisting MEK1(P124) mutations are associated with a reduced response to BRAF inhibitor therapy and identify a subset of patients with BRAF-mutant melanoma likely to benefit from combination therapies involving MEK or ERK inhibitors.

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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	K57E	missense	gain of function	MAP2K1 K57E lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). K57E confers a gain of function to Map2k1 as demonstrated by increased activation of downstream Erk1/2 (PMID: 24463458, PMID: 25370473) and increased transformation in cultured cells and increased proliferation in a competition assay (PMID: 36442478), and is associated with Braf inhibitor resistance in cell culture (PMID: 24463458, PMID: 25370473, PMID: 36442478).	Y
MAP2K1	P124Q	missense	unknown	MAP2K1 P124Q lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P124Q results in increased Erk1/2 phosphorylation in culture, and is associated with decreased sensitivity to Raf inhibition (PMID: 25370473), but demonstrates autophosphorylation and kinase activity similar to wild-type Map2k1 in another study (PMID: 29753091), and therefore, its effect on Map2k1 protein function is unknown.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600K MAP2K1 P124L	melanoma	decreased response	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF V600K and MAP2K1 P124L demonstrated decreased sensitivity to Tafinlar (dabrafenib) in culture (PMID: 25370473).	25370473
BRAF V600K MAP2K1 P124Q	melanoma	sensitive	VX-11e	Preclinical - Cell culture	Actionable	In a preclinical study, VX-11e inhibited ERK signaling and reduced growth of a melanoma cell line harboring BRAF V600K and MAP2K1 P124Q in culture (PMID: 25370473).	25370473
BRAF V600K MAP2K1 P124Q	melanoma	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited ERK signaling and reduced growth of a melanoma cell line harboring BRAF V600K and MAP2K1 P124Q in culture (PMID: 25370473).	25370473
BRAF V600E MAP2K1 P124Q	melanoma	decreased response	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 P124Q demonstrated decreased sensitivity to Tafinlar (dabrafenib) in cell culture (PMID: 25370473).	25370473
BRAF V600E MAP2K1 K57E	melanoma	resistant	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 K57E in a melanoma cell line harboring BRAF V600E conferred resistance to Tafinlar (dabrafenib) in culture (PMID: 25370473).	25370473
BRAF V600K MAP2K1 P124Q	melanoma	decreased response	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring BRAF V600K and MAP2K1 P124Q demonstrated decreased sensitivity to Tafinlar (dabrafenib) in culture (PMID: 25370473).	25370473
BRAF V600K MAP2K1 P124L	melanoma	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited ERK signaling and reduced growth of a melanoma cell line harboring BRAF V600K and MAP2K1 P124L in culture (PMID: 25370473).	25370473
BRAF V600K MAP2K1 P124L	melanoma	sensitive	VX-11e	Preclinical	Actionable	In a preclinical study, VX-11e inhibited ERK signaling and reduced growth of a melanoma cell line harboring BRAF V600K and MAP2K1 P124L in culture (PMID: 25370473).	25370473