Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells.
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.
Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom.|Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom.
Lindsay C
LC
Spender
Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom.|Department of Respiratory, Inflammation and Autoimmunity Research, MedImmune Limited, Cambridge, United Kingdom.
G John
GJ
Ferguson
Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Einthovenweg, Leiden, Netherlands.
Sijia
S
Liu
Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Einthovenweg, Leiden, Netherlands.
Chao
C
Cui
Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Withington, Manchester, United Kingdom.
Maria Romina
MR
Girotti
Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom.
Gary
G
Sibbet
Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom.
Ellen B
EB
Higgs
Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom.
Morven K
MK
Shuttleworth
Biological Services, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom.
Tom
T
Hamilton
The University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom.
Paul
P
Lorigan
Department of Neurology, University Hospital Zurich, Frauenklinikstrasse, Zurich, Switzerland.
Michael
M
Weller
Colorectal Cancer and Wnt Signalling, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom.
David F
DF
Vincent
Colorectal Cancer and Wnt Signalling, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom.
Owen J
OJ
Sansom
The Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
Margaret
M
Frame
Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Einthovenweg, Leiden, Netherlands.
Peter Ten
PT
Dijke
Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Withington, Manchester, United Kingdom.
Richard
R
Marais
Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Bearsden, Glasgow, United Kingdom.|Division of Cancer Research, School of Medicine, University of Dundee, Dundee, United Kingdom.
Gareth J
GJ
Inman
D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008544:Melanocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D004149:Dioxoles; D007211:Indoles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; D000077484:Vemurafenib; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
BRAF; PLX-4720; TGF-beta; melanoma; vemurafenib