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
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85053177047&doi=10.1158%2f2159-8290.CD-17-1263&partnerID=40&md5=2922845e1a40ddaac91a23879bd7daba
Notes:	Article -- Export Date: 1 October 2018 -- Source: Scopus

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