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

TY - JOUR

T1 - Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells

AU - Spender, Lindsay C.

AU - Ferguson, G. John

AU - Liu, Sijia

AU - Cui, Chao

AU - Girotti, Maria Romina

AU - Sibbet, Gary

AU - Higgs, Ellen B.

AU - Shuttleworth, Morven K.

AU - Hamilton, Tom

AU - Lorigan, Paul

AU - Weller, Michael

AU - Vincent, David F.

AU - Sansom, Owen J.

AU - Frame, Margaret

AU - Ten Dijke, Peter

AU - Marais, Richard

AU - Inman, Gareth J.

N1 - Financial support: GJI, LCS, GJF, GS, TH, OJS and DFV were supported by the CRUK Beatson Institute. LS was also funded by a Worldwide Cancer Research (formerly AICR) project grant to GJI (11-078). MRG and RM are supported by the CRUK Manchester Institute [C5759/A12328] and the Wellcome Trust [100282/Z/12/Z]. SL, CC and PtD are supported by the Cancer Genomics Centre, Netherlands.

PY - 2016/12/13

Y1 - 2016/12/13

N2 - 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.

AB - 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.

KW - melanoma

KW - BRAF

KW - verurafenib

KW - PLX-4720

KW - TFG-beta

U2 - 10.18632/oncotarget.13226

DO - 10.18632/oncotarget.13226

M3 - Article

C2 - 27835901

SN - 1949-2553

VL - 7

SP - 81995

EP - 82012

JO - Oncotarget

JF - Oncotarget

IS - 50

ER -