A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAFV600E-mutant brain tumor Academic Article uri icon

Overview

MeSH Major

  • Aneurysm, Dissecting
  • Aortic Aneurysm, Abdominal
  • Aortic Aneurysm, Thoracic
  • Postoperative Complications
  • Reoperation
  • Vascular Surgical Procedures

abstract

  • ©2018 American Association for Cancer Research. BRAFV600Ehyperactivates ERK and signals as a RAF inhibitor–sensitive monomer. Although RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAFV600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAFL514Vmutation at progression that was not present in the pretreatment tumor. Expressing BRAFV600E/L514Vinduces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. Newer RAF dimer inhibitors and an ERK inhibitor are effective against BRAFL514V-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that, like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence. SIGnIFICAnCE: In contrast to receptor tyrosine kinases, in which secondary mutations are often responsible for acquired resistance, second-site mutations in BRAF have not been validated in clinically acquired resistance to RAF inhibitors. We demonstrate a secondary mutation in BRAF (V600E/ L514V) following progression on dabrafenib and confirm functionally that this mutation is responsible for resistance.

publication date

  • September 2018

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-17-1263

Additional Document Info

start page

  • 1130

end page

  • 1141

volume

  • 8

number

  • 9