Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells.
Authors
Spender, LFerguson, G
Liu, S
Cui, C
Girotti, Maria Romina
Sibbet, G
Higgs, E
Shuttleworth, M
Hamilton, T
Lorigan, Paul C
Weller, M
Vincent, D
Sansom, O
Frame, M
Ten Dijke, P
Marais, R
Inman, G
Affiliation
Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Bearsden, GlasgowIssue Date
2016-11-09
Metadata
Show full item recordAbstract
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.Citation
Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells. 2016, OncotargetJournal
OncotargetDOI
10.18632/oncotarget.13226PubMed ID
27835901Type
ArticleLanguage
enISSN
1949-2553ae974a485f413a2113503eed53cd6c53
10.18632/oncotarget.13226
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