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Identification of PLX 4032‐resistance mechanisms and implications for novel RAF inhibitors
Author(s) -
Choi Jaehyuk,
Landrette Sean F.,
Wang Tiffany,
Evans Perry,
Bacchiocchi Antonella,
Bjornson Robert,
Cheng Elaine,
Stiegler Amy L.,
Gathiaka Symon,
Acevedo Orlando,
Boggon Titus J.,
Krauthammer Michael,
Halaban Ruth,
Xu Tian
Publication year - 2014
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12197
Subject(s) - melanoma , mutation , cancer research , mutagenesis , exome sequencing , mutant , vemurafenib , biology , genetics , gene , metastatic melanoma
Summary BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel BRAF mutation that confers resistance to PLX 4032 employing whole‐exome sequencing of drug‐resistant BRAF V600K melanoma cells. We further describe a new screening approach, a genome‐wide piggy B ac mutagenesis screen that revealed clinically relevant aberrations ( N ‐terminal BRAF truncations and CRAF overexpression). The novel BRAF mutation, a L eu505 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 ‐ PLX 4032 interface with a larger polar residue. Moreover, we show that BRAF L505H , found in human prostate cancer, is itself a MAPK ‐activating, PLX 4032‐resistant oncogenic mutation. Lastly, we demonstrate that the PLX 4032‐resistant melanoma cells are sensitive to novel, next‐generation BRAF inhibitors, especially the ‘paradox‐blocker’ PLX 8394, supporting its use in clinical trials for treatment of melanoma patients with BRAF ‐mutations.