A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAF(V600E)-mutant brain tumor Journal Article

Authors: Wang, J.; Yao, Z.; Jonsson, P.; Allen, A. N.; Qin, A. C. R.; Uddin, S.; Dunkel, I. J.; Petriccione, M.; Manova, K.; Haque, S.; Rosenblum, M. K.; Pisapia, D. J.; Rosen, N.; Taylor, B. S.; Pratilas, C. A.
Article Title: A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAF(V600E)-mutant brain tumor
Abstract: BRAFV600E hyperactivates 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 BRAFL514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAFV600E/L514V induces 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. ©2018 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 8
Issue: 9
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2018-09-01
Start Page: 1130
End Page: 1141
Language: English
DOI: 10.1158/2159-8290.cd-17-1263
PROVIDER: scopus
PMCID: PMC6125191
PUBMED: 29880583
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
Citation Impact
MSK Authors
  1. Ira J Dunkel
    316 Dunkel
  2. Neal Rosen
    399 Rosen
  3. Marc Rosenblum
    369 Rosenblum
  4. Sofia S Haque
    116 Haque
  5. Barry Stephen Taylor
    226 Taylor
  6. Zhan Yao
    37 Yao
  7. Sharmeen Yeasmin Uddin
    5 Uddin
  8. Karl Philip Jonsson
    47 Jonsson