In:
Pigment Cell & Melanoma Research, Wiley, Vol. 27, No. 2 ( 2014-03), p. 253-262
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 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.
Type of Medium:
Online Resource
ISSN:
1755-1471
,
1755-148X
DOI:
10.1111/pcmr.2014.27.issue-2
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2425880-5
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