RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E) Journal Article

   

Authors:	Poulikakos, P. I.; Persaud, Y.; Janakiraman, M.; Kong, X.; Ng, C.; Moriceau, G.; Shi, H.; Atefi, M.; Titz, B.; Gabay, M. T.; Salton, M.; Dahlman, K. B.; Tadi, M.; Wargo, J. A.; Flaherty, K. T.; Kelley, M. C.; Misteli, T.; Chapman, P. B.; Sosman, J. A.; Graeber, T. G.; Ribas, A.; Lo, R. S.; Rosen, N.; Solit, D. B.
Article Title:	RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
Abstract:	Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner. © 2011 Macmillan Publishers Limited. All rights reserved.
Keywords:	mitogen activated protein kinase; human tissue; exon; mutation; exons; drug activity; raf protein; protein domain; sensitivity analysis; animals; mice; melanoma; map kinase signaling system; signaling; protein binding; drug resistance, neoplasm; cell line, tumor; inhibitor; mutational analysis; protein kinase inhibitors; protein multimerization; sulfonamides; alternative splicing; extracellular signal-regulated map kinases; dimerization; mutant proteins; indoles; b raf kinase; protein isoforms; proto-oncogene proteins b-raf; rna splicing; inhibition; skin disorder; drug; vemurafenib
Journal Title:	Nature
Volume:	480
Issue:	7377
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2011-12-01
Start Page:	387
End Page:	390
Language:	English
DOI:	10.1038/nature10662
PROVIDER:	scopus
PUBMED:	22113612
PMCID:	PMC3266695
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-83455254767&partnerID=40&md5=d25595171161c798ce2c733d697e1d16
Notes:	--- - "Cited By (since 1996): 1" - "Export Date: 3 January 2012" - "CODEN: NATUA" - "Source: Scopus"

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