Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells.
Spender, L Ferguson, G Liu, S Cui, C Girotti, Maria Romina Sibbet, G Higgs, E Shuttleworth, M Hamilton, T Lorigan, Paul C
Spender, L
Ferguson, G
Liu, S
Cui, C
Girotti, Maria Romina
Sibbet, G
Higgs, E
Shuttleworth, M
Hamilton, T
Lorigan, Paul C
Citations
Altmetric:
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.
Description
Date
2016-11-09
Publisher
Collections
Keywords
Type
Article
Citation
Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells. 2016, Oncotarget