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Ref Type Journal Article
PMID (24463458)
Authors Rizos H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J, Haydu LE, Mijatov B, Becker TM, Boyd SC, Howle J, Saw R, Thompson JF, Kefford RF, Scolyer RA, Long GV
Title BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 20
Issue 7
Date 2014 Apr 01
URL
Abstract Text Multiple BRAF inhibitor resistance mechanisms have been described, however, their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma.Fifty-nine BRAF(V600)-mutant melanoma metastases from patients treated with dabrafenib or vemurafenib were analyzed. The genetic profile of resistance mechanisms and tumor signaling pathway activity was correlated with clinicopathologic features and therapeutic outcomes.Resistance mechanisms were identified in 58% progressing tumors and BRAF alterations were common. Gene expression analysis revealed that mitogen-activated protein kinase (MAPK) activity remained inhibited in 21% of resistant tumors, and the outcomes of patients with these tumors were poor. Resistance mechanisms also occurred in pretreatment biopsies and heterogeneity of resistance mechanisms occurred within patients and within tumors. There were no responses to subsequent targeted therapy, even when a progressing tumor had a resistance mechanism predicted to be responsive.Selecting sequential drugs based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved responses, and first-line therapies targeting multiple pathways will be required.

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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 K57C missense gain of function - predicted MAP2K1 K57C lies within the negative regulatory region of the Map2k1 protein (PMID: 24241536). K57C has not been biochemically characterized, however, results in restored pathway activation in the presence of an upstream pathway inhibitor (PMID: 24463458), and therefore, is predicted to result in a gain of Map2k1 protein function.
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 on the Map2k1 protein as demonstrated by increased activation of downstream Erk1/2 and has been associated with Braf inhibitor resistance in cell culture (PMID: 24463458, PMID: 25370473). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 K57E melanoma resistant Dabrafenib Preclinical Actionable In a preclinical study, MAP2K1 (MEK1) K57E mutations restored extracellular signal-regulated kinase (ERK) activation in the presence of Tafinlar (dabrafenib) in cultured melanoma cell lines (PMID: 24463458). 24463458