Identification of PLX4032-Resistance Mechanisms and Implications for Novel RAF Inhibitors
Menée in vitro, cette étude met en évidence un mécanisme par lequel une mutation du gène BRAF (L505H) confère une résistance au vémurafenib, puis montre que les cellules de mélanome présentant cette mutation sont sensibles à une nouvelle génération d'inhibiteurs de BRAF tel que le composé appelé PLX8394
BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of novel BRAF mutation that confers resistance to PLX4032 employing whole-exome sequencing of drug-resistant BRAFV600K melanoma cells, BRAF Leu505 to His substitution (BRAFL505H) and describe a new screening approach, a genome-wide piggyBac mutagenesis screen that revealed clinically relevant aberrations (N-terminal BRAF truncations and CRAF overexpression). The BRAFL505H 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 BRAFL505H, 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. This article is protected by copyright. All rights reserved.