Priority Research Papers:
Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells
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Lindsay C. Spender1,9, G. John Ferguson1,10, Sijia Liu4, Chao Cui4, Maria Romina Girotti5, Gary Sibbet1, Ellen B. Higgs9, Morven K. Shuttleworth9, Tom Hamilton2, Paul Lorigan6, Michael Weller7, David F. Vincent3, Owen J. Sansom3, Margaret Frame8, Peter ten Dijke4, Richard Marais5 and Gareth J. Inman1,9
1 Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom
2 Biological Services, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom
3 Colorectal Cancer and Wnt Signalling, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom
4 Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Einthovenweg, Leiden, Netherlands
5 Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Withington, Manchester, United Kingdom
6 The University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom
7 Department of Neurology, University Hospital Zurich, Frauenklinikstrasse, Zurich, Switzerland
8 The Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
9 Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom
10 Department of Respiratory, Inflammation and Autoimmunity Research, MedImmune Limited, Cambridge, United Kingdom
Gareth J. Inman, email:
Keywords: melanoma, BRAF, vemurafenib, PLX-4720, TGF-beta
Received: February 15, 2016 Accepted: July 18, 2016 Published: November 09, 2016
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.
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