Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells

Lindsay C. Spender, G. John Ferguson, Sijia Liu, Chao Cui, Maria Romina Girotti, Gary Sibbet, Ellen B. Higgs, Morven K. Shuttleworth, Tom Hamilton, Paul Lorigan, Michael Weller, David F. Vincent, Owen J. Sansom, Margaret Frame, Peter Ten Dijke, Richard Marais, Gareth J. Inman (Lead / Corresponding author)

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    Abstract

    Recent data implicate elevated transforming growth factor-β (TGFβ) signalling in BRAF inhibitor drug-resistance mechanisms, but the potential for targeting TGFβ signalling in cases of advanced melanoma has not been investigated. We show that mutant BRAFV600E confers an intrinsic dependence on TGFβ/TGFβ receptor 1 (TGFBR1) signalling for clonogenicity of murine melanocytes. Pharmacological inhibition of the TGFBR1 blocked the clonogenicity of human mutant BRAF melanoma cells through SMAD4-independent inhibition of mitosis, and also inhibited metastasis in xenografted zebrafish. When investigating the therapeutic potential of combining inhibitors of mutant BRAF and TGFBR1, we noted that unexpectedly, low-dose PLX-4720 (a vemurafenib analogue) promoted proliferation of drug-naïve melanoma cells. Pharmacological or pharmacogenetic inhibition of TGFBR1 blocked growth promotion and phosphorylation of SRC, which is frequently associated with vemurafenib-resistance mechanisms. Importantly, vemurafenib-resistant patient derived cells retained sensitivity to TGFBR1 inhibition, suggesting that TGFBR1 could be targeted therapeutically to combat the development of vemurafenib drug-resistance.

    Original languageEnglish
    Pages (from-to)81995-82012
    Number of pages18
    JournalOncotarget
    Volume7
    Issue number50
    Early online date9 Nov 2016
    DOIs
    Publication statusPublished - 13 Dec 2016

    Keywords

    • melanoma
    • BRAF
    • verurafenib
    • PLX-4720
    • TFG-beta

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    Cite this

    Spender, L. C., Ferguson, G. J., Liu, S., Cui, C., Girotti, M. R., Sibbet, G., Higgs, E. B., Shuttleworth, M. K., Hamilton, T., Lorigan, P., Weller, M., Vincent, D. F., Sansom, O. J., Frame, M., Ten Dijke, P., Marais, R., & Inman, G. J. (2016). Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells. Oncotarget, 7(50), 81995-82012. https://doi.org/10.18632/oncotarget.13226