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

Jaehyuk Choi*, Sean F. Landrette, Tiffany Wang, Perry Evans, Antonella Bacchiocchi, Robert Bjornson, Elaine Cheng, Amy L. Stiegler, Symon Gathiaka, Orlando Acevedo, Titus J. Boggon, Michael Krauthammer, Ruth Halaban, Tian Xu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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 BRAFV600K 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 (BRAFL505H), 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 BRAFL505H, 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.

Original languageEnglish (US)
Pages (from-to)253-262
Number of pages10
JournalPigment Cell and Melanoma Research
Issue number2
StatePublished - Mar 2014


  • BRAF
  • Drug resistance
  • Melanoma
  • PLX4032
  • Paradox blockers

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • Dermatology
  • Oncology


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