BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors.
Cancer Discov
; 2(9): 791-7, 2012 Sep.
Article
en En
| MEDLINE
| ID: mdl-22798288
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Piridonas
/
Pirimidinonas
/
Quinasas Quinasa Quinasa PAM
/
Proteínas Proto-Oncogénicas B-raf
/
Inhibidores de Proteínas Quinasas
/
Melanoma
/
Mutación
Tipo de estudio:
Diagnostic_studies
/
Risk_factors_studies
Límite:
Aged
/
Humans
/
Male
Idioma:
En
Revista:
Cancer Discov
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos