Identification of PLX4032‐resistance mechanisms and implications for novel RAF inhibitors. (6th January 2014)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Pigment cell & melanoma research. Volume 27:Number 2(2014:Mar.)
• Page Start: 253
• Page End: 262
• Publication Date: 2014-01-06
• Subjects: Melanoma -- Periodicals; Chromatophores -- Periodicals; Animal pigments -- Periodicals; 616.99477
• DOI: 10.1111/pcmr.12197
• Languages: English
• ISSNs: 1755-1471

Abstract

<abstract abstract-type="main" id="pcmr12197-abs-0001"> <title>Summary</title> <p>BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel <italic>BRAF</italic> mutation that confers resistance to PLX4032 employing whole‐exome sequencing of drug‐resistant <italic>BRAF</italic>^{<italic>V600K</italic>} melanoma cells. We further describe a new screening approach, a genome‐wide <italic>piggyBac</italic> mutagenesis screen that revealed clinically relevant aberrations (N‐terminal <italic>BRAF</italic> truncations and <italic>CRAF</italic> overexpression). The novel <italic>BRAF</italic> mutation, a Leu505 to His substitution (<italic>BRAF</italic>^{<italic>L505H</italic>}), is the first resistance‐conferring second‐site mutation identified in <italic>BRAF</italic> mutant cells. The mutation replaces a small nonpolar amino acid at the BRAF‐PLX4032 interface with a larger polar residue. Moreover, we show that <italic>BRAF</italic>^{<italic>L505H</italic>}, 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.</p> </abstract>