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

Maayan Salton, Wojciech K. Kasprzak, Ty Voss, Bruce A. Shapiro, Poulikos I. Poulikakos and Tom Misteli ()
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Maayan Salton: National Cancer Institute, NIH, Cell Biology of Genomes Group
Wojciech K. Kasprzak: Leidos Biomedical Research, Inc., Basic Science Program, Frederick National Laboratory
Ty Voss: National Cancer Institute, NIH, Cell Biology of Genomes Group
Bruce A. Shapiro: National Cancer Institute, NIH
Poulikos I. Poulikakos: Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute
Tom Misteli: National Cancer Institute, NIH, Cell Biology of Genomes Group

Nature Communications, 2015, vol. 6, issue 1, 1-7

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms8103

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