PUBLICATION
Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells
- 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., Ten Dijke, P., Marais, R., Inman, G.J.
- ID
- ZDB-PUB-161113-9
- Date
- 2016
- Source
- Oncotarget 7(50): 81995-82012 (Journal)
- Registered Authors
- Keywords
- BRAF, PLX-4720, TGF-beta, melanoma, vemurafenib
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Antineoplastic Agents/pharmacology*
- Benzamides/pharmacology*
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Dioxoles/pharmacology*
- Dose-Response Relationship, Drug
- Drug Resistance, Neoplasm/drug effects*
- Drug Resistance, Neoplasm/genetics
- Humans
- Indoles/pharmacology*
- Melanocytes/drug effects
- Melanocytes/enzymology
- Melanocytes/pathology
- Melanoma/drug therapy*
- Melanoma/enzymology
- Melanoma/genetics
- Melanoma/pathology
- Mice, Nude
- Mitosis/drug effects
- Mutation*
- Protein Kinase Inhibitors/pharmacology*
- Protein Serine-Threonine Kinases/antagonists & inhibitors*
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- Proto-Oncogene Proteins B-raf/antagonists & inhibitors*
- Proto-Oncogene Proteins B-raf/genetics
- Proto-Oncogene Proteins B-raf/metabolism
- RNA Interference
- Receptors, Transforming Growth Factor beta/antagonists & inhibitors*
- Receptors, Transforming Growth Factor beta/genetics
- Receptors, Transforming Growth Factor beta/metabolism
- Signal Transduction/drug effects
- Skin Neoplasms/drug therapy*
- Skin Neoplasms/enzymology
- Skin Neoplasms/genetics
- Skin Neoplasms/pathology
- Smad4 Protein/genetics
- Smad4 Protein/metabolism
- Sulfonamides/pharmacology*
- Time Factors
- Transfection
- Transforming Growth Factor beta1/pharmacology
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 27835901 Full text @ Oncotarget
Citation
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.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping