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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

1
National Cancer Institute, NIH, Cell Biology of Genomes Group, Bethesda, Maryland 20892, USA.
2
Leidos Biomedical Research, Inc., Basic Science Program, Frederick National Laboratory, Frederick, Maryland 21702 USA.
3
National Cancer Institute, NIH, Frederick, RNA Structure and Design Section, Maryland 21702, USA.
4
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.

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.

PMID:
25971842
PMCID:
PMC4435825
DOI:
10.1038/ncomms8103
[Indexed for MEDLINE]
Free PMC Article

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