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.
Keywords:
BRAF; PLX-4720; TGF-beta; melanoma; vemurafenib.
MeSH terms
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Animals
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Animals, Genetically Modified
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Antineoplastic Agents / pharmacology*
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Benzamides / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dioxoles / pharmacology*
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Humans
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Indoles / pharmacology*
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Melanocytes / drug effects
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Melanocytes / enzymology
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Melanocytes / pathology
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Melanoma / drug therapy*
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Melanoma / enzymology
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Melanoma / genetics
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Melanoma / pathology
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Mice, Nude
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Mitosis / drug effects
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Mutation*
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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RNA Interference
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / drug effects
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Skin Neoplasms / drug therapy*
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Skin Neoplasms / enzymology
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Skin Neoplasms / genetics
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Skin Neoplasms / pathology
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Smad4 Protein / genetics
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Smad4 Protein / metabolism
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Sulfonamides / pharmacology*
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Time Factors
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Transfection
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Transforming Growth Factor beta1 / pharmacology
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Vemurafenib
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Xenograft Model Antitumor Assays
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Zebrafish
Substances
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4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
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Antineoplastic Agents
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Benzamides
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Dioxoles
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Indoles
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PLX 4720
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Protein Kinase Inhibitors
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Receptors, Transforming Growth Factor beta
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SMAD4 protein, human
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Smad4 Protein
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Sulfonamides
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Transforming Growth Factor beta1
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Vemurafenib
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BRAF protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins B-raf
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, mouse