Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors.
Pigment Cell Melanoma Res
; 27(2): 253-62, 2014 Mar.
Article
em En
| MEDLINE
| ID: mdl-24283590
ABSTRACT
BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel BRAF mutation that confers resistance to PLX4032 employing whole-exome sequencing of drug-resistant BRAF(V600K) melanoma cells. We further describe a new screening approach, a genome-wide piggyBac mutagenesis screen that revealed clinically relevant aberrations (N-terminal BRAF truncations and CRAF overexpression). The novel BRAF mutation, a Leu505 to His substitution (BRAF(L505H) ), is the first resistance-conferring second-site mutation identified in BRAF mutant cells. The mutation replaces a small nonpolar amino acid at the BRAF-PLX4032 interface with a larger polar residue. Moreover, we show that BRAF(L505H) , found in human prostate cancer, is itself a MAPK-activating, PLX4032-resistant oncogenic mutation. Lastly, we demonstrate that the PLX4032-resistant melanoma cells are sensitive to novel, next-generation BRAF inhibitors, especially the 'paradox-blocker' PLX8394, supporting its use in clinical trials for treatment of melanoma patients with BRAF-mutations.
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MEDLINE
Assunto principal:
Sulfonamidas
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Resistencia a Medicamentos Antineoplásicos
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Proteínas Proto-Oncogênicas B-raf
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Inibidores de Proteínas Quinases
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Indóis
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article