IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v6y2015i1d10.1038_ncomms8103.html
   My bibliography  Save this article

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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Maayan Salton & Wojciech K. Kasprzak & Ty Voss & Bruce A. Shapiro & Poulikos I. Poulikakos & Tom Misteli, 2015. "Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing," Nature Communications, Nature, vol. 6(1), pages 1-7, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8103
    DOI: 10.1038/ncomms8103
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms8103
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms8103?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8103. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.