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

Spender, L. C. et al. (2016) Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells. Oncotarget, 7(50), pp. 81995-82012. (doi: 10.18632/oncotarget.13226) (PMID:27835901) (PMCID:PMC5347669)

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.

• Item Type: Articles
• Additional Information: Financial support: GJI, LCS, GJF, GS, TH, OJS and DFV were supported by the CRUK Beatson Institute. LS was also funded by a Worldwide Cancer Research (formerly AICR) project grant to GJI (11-078). MRG and RM are supported by the CRUK Manchester Institute [C5759/A12328] and the Wellcome Trust [100282/Z/12/Z]. SL, CC and PtD are supported by the Cancer Genomics Centre, Netherlands.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Inman, Professor Gareth and Sibbet, Dr Gary and Spender, Dr Lindsay and Vincent, Dr David and Sansom, Professor Owen
• Authors: 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., Dijke, P. t., Marais, R., and Inman, G. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncotarget
• Publisher: Impact Journals
• ISSN: 1949-2553
• ISSN (Online): 1949-2553
• Published Online: 09 November 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Oncotarget 7(50): 81995-82012
• Publisher Policy: Reproduced under a Creative Commons License