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Nat Commun. 2015 May 14;6:7103. doi: 10.1038/ncomms8103.

Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing.

Author information

National Cancer Institute, NIH, Cell Biology of Genomes Group, Bethesda, Maryland 20892, USA.
Leidos Biomedical Research, Inc., Basic Science Program, Frederick National Laboratory, Frederick, Maryland 21702 USA.
National Cancer Institute, NIH, Frederick, RNA Structure and Design Section, Maryland 21702, USA.
Icahn School of Medicine at Mount Sinai, Department of Oncological Sciences and Department of Dermatology, The Tisch Cancer Institute, New York, New York 10029, USA.


Mutations in the serine/threonine kinase BRAF are found in more than 60% of melanomas. The most prevalent melanoma mutation is BRAF(V600E), which constitutively activates downstream MAPK signalling. Vemurafenib is a potent RAF kinase inhibitor with remarkable clinical activity in BRAF(V600E)-positive melanoma tumours. However, patients rapidly develop resistance to vemurafenib treatment. One resistance mechanism is the emergence of BRAF alternative splicing isoforms leading to elimination of the RAS-binding domain. Here we identify interference with pre-mRNA splicing as a mechanism to combat vemurafenib resistance. We find that small-molecule pre-mRNA splicing modulators reduce BRAF3-9 production and limit in-vitro cell growth of vemurafenib-resistant cells. In xenograft models, interference with pre-mRNA splicing prevents tumour formation and slows growth of vemurafenib-resistant tumours. Our results identify an intronic mutation as the molecular basis for a RNA splicing-mediated RAF inhibitor resistance mechanism and we identify pre-mRNA splicing interference as a potential therapeutic strategy for drug resistance in BRAF melanoma.

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