Journal
NATURE
Volume 480, Issue 7377, Pages 387-U144Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature10662
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Categories
Funding
- Vanderbilt-Ingram Cancer Center
- T. J. Martell Foundation
- National Institutes of Health (NIH)
- Beene Foundation
- Melanoma Research Alliance
- STARR Foundation
- Burroughs Wellcome Fund
- American Skin Association
- Joint Center for Translational Medicine
- Sidney Kimmel Foundation
- Stand Up to Cancer
- NIH, NCI, Center for Cancer Research
- Danny Federici Melanoma Fund
- [T32 CACA062948-15]
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Activated RAS promotes dimerization of members of the RAF kinase family(1-3). ATP-competitive RAF inhibitors activate ERK signalling(4-7) by transactivating RAF dimers(4). 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)(8). 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.
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