BRAF L597 Mutations in Melanoma Are Associated with Sensitivity to MEK Inhibitors
Year: 2012
Type: article
Abstract: UNLABELLED: 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. SIGNIFICANCE: 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.
Source: Cancer Discovery
Authors: Kimberly Brown Dahlman, Junfeng Xia, Katherine Hutchinson, Charles Ng, Donald Hucks, Peilin Jia, Mohammad Atefi, Zengliu Su, Suzanne Branch, Pamela L. Lyle, Donna J. Hicks, Viviana Bozon, John A. Glaspy, Neal Rosen, David B. Solit, James L. Netterville, Cindy L. Vnencak-Jones, Jeffrey A. Sosman, Antoni Ribas, Zhongming Zhao, William Pao
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Genentech, National Cancer Institute
OpenAlex ID: W2128327828