Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells.

ABSTRACT: Recent data implicate elevated transforming growth factor-? (TGF?) signalling in BRAF inhibitor drug-resistance mechanisms, but the potential for targeting TGF? signalling in cases of advanced melanoma has not been investigated. We show that mutant BRAFV600E confers an intrinsic dependence on TGF?/TGF? 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.

SUBMITTER: Spender LC 

PROVIDER: S-EPMC5347669 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature