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Ref Type Journal Article
PMID (22798288)
Authors Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, Atefi M, Su Z, Branch S, Lyle PL, Hicks DJ, Bozon V, Glaspy JA, Rosen N, Solit DB, Netterville JL, Vnencak-Jones CL, Sosman JA, Ribas A, Zhao Z, Pao W
Title BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 2 9 2012 Sep 791-7 Cancer Discov
URL
Abstract Text Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40% to 50% of cases are positive. To uncover other potential targetable mutations, we conducted whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, and D816) wild-type melanoma. Surprisingly, we found a somatic BRAF(L597R) mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAF(V600) mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that two (4%) harbored L597 mutations and another two involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition. A patient with BRAF(L597S) mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data show clinical significance to BRAF(L597) mutations in melanoma.This study shows that cells harboring BRAF(L597R) mutants are sensitive to MEK inhibitor treatment, providing a rationale for routine screening and therapy of BRAF(L597R)-mutant melanoma.

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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
BRAF K601E missense gain of function BRAF K601E lies within the activation segment in the kinase domain of the Braf protein (PMID: 15343278). K601E results in increased Braf kinase activity and downstream activation of MEK and ERK in cell culture (PMID: 22798288, PMID: 28783719, PMID: 32059434), and induces cell proliferation and cell viability in culture (PMID: 29533785, PMID: 18697864).
BRAF L597Q missense gain of function BRAF L597Q lies within the protein kinase domain of the Braf protein (UniProt.org). L597Q results in activation of Braf as indicated by increased phosphorylation of Mek and Erk in cell culture (PMID: 22798288) and induces cell proliferation and cell viability in culture (PMID: 29533785).
BRAF L597R missense gain of function BRAF L597R lies within the protein kinase domain of the Braf protein (UniProt.org). L597R results in activation of Braf as indicated by increased phosphorylation of Mek and Erk in cell culture (PMID: 22798288, PMID: 26343582), is associated with Erk activation in a patient tumor sample (PMID: 23715574), and in one of two cell lines, increased cell proliferation and cell viability compared to wild-type Braf (PMID: 29533785).
BRAF L597S missense gain of function BRAF L597S lies within the protein kinase domain of the Braf protein (UniProt.org). L597S results in activation of Braf as indicated by increased phosphorylation of Mek and Erk in cell culture (PMID: 22798288) and induces cell proliferation and cell viability in culture (PMID: 29533785).
BRAF L597V missense gain of function BRAF L597V lies within the protein kinase domain of the Braf protein (UniProt.org). L597V results in activation of Braf as indicated by increased phosphorylation of Mek and Erk in cell culture (PMID: 22798288) and and induces cell proliferation and cell viability in culture (PMID: 29533785).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF L597S Advanced Solid Tumor sensitive Trametinib Preclinical Actionable Preclinical studies demonstrated the MEK inhibitor, Mekinist (trametinib) caused decreased activation of MEK and ERK in cells expressing BRAF L597S (PMID: 22798288). 22798288
BRAF L597S Advanced Solid Tumor sensitive Vemurafenib Preclinical Actionable In a preclinical study, treatment of cells expressing BRAF L597S with the BRAF inhibitor, Zelboraf (vemurafenib), decreased activation of MEK and ERK (PMID: 22798288). 22798288
BRAF K601E Advanced Solid Tumor conflicting Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, treatment of cells expressing BRAF K601E with the BRAF inhibitor, Zelboraf (vemurafenib), decreased activation of MEK and ERK (PMID: 22798288). 22798288
BRAF K601E Advanced Solid Tumor sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, the MEK inhibitor, Mekinist (trametinib) decreased activation of MEK and ERK in cells expressing BRAF K601E in culture (PMID: 22798288). 22798288
BRAF L597R Advanced Solid Tumor sensitive Trametinib Preclinical Actionable Preclinical studies demonstrated the MEK inhibitor, Mekinist (trametinib) caused decreased activation of MEK and ERK in cells expressing BRAF L597R (PMID: 22798288). 22798288
BRAF L597S melanoma predicted - sensitive TAK-733 Case Reports/Case Series Actionable In a Phase I trial, TAK-733 treatment resulted in a partial response after 2 cycles in a patient with metastatic melanoma harboring BRAF L597S, who remained progression-free for over 24 weeks (PMID: 22798288). 22798288
BRAF L597R Advanced Solid Tumor sensitive Vemurafenib Preclinical Actionable In a preclinical study, treatment of cells expressing BRAF L597R with the BRAF inhibitor, Zelboraf (vemurafenib), decreased activation of MEK and ERK (PMID: 22798288). 22798288