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Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors.
- Source :
- Pigment Cell & Melanoma Research; Mar2014, Vol. 27 Issue 2, p253-262, 10p
- Publication Year :
- 2014
-
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<superscript> V600K</superscript> melanoma cells. We further describe a new screening approach, a genome-wide piggy Bac mutagenesis screen that revealed clinically relevant aberrations ( N-terminal BRAF truncations and CRAF overexpression). The novel BRAF mutation, a Leu505 to His substitution ( BRAF<superscript> L505H</superscript>), 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<superscript> L505H</superscript>, 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 17551471
- Volume :
- 27
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Pigment Cell & Melanoma Research
- Publication Type :
- Academic Journal
- Accession number :
- 94448065
- Full Text :
- https://doi.org/10.1111/pcmr.12197