Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors.

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.

authors

Choi J,Landrette SF,Wang T,Evans P,Bacchiocchi A,Bjornson R,Cheng E,Stiegler AL,Gathiaka S,Acevedo O,Boggon TJ,Krauthammer M,Halaban R,Xu T

doi

10.1111/pcmr.12197

subject

Has Abstract

pub_date

2014-03-01 00:00:00

pages

253-62

issue

2

eissn

1755-1471

issn

1755-148X

journal_volume

27

pub_type

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