Reference Detail

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
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	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 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
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	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	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 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