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

Lindsay C. Spender; G. John Ferguson; Sijia Liu; Chao Cui; Maria Romina Girotti; Gary Sibbet; Ellen B. Higgs; Morven K. Shuttleworth; Tom Hamilton; Paul Lorigan; Michael Weller; David F. Vincent; Owen J. Sansom; Margaret Frame; Peter Ten Dijke; Richard Marais; Gareth J. Inman

doi:10.18632/oncotarget.13226

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

Lindsay C. Spender, G. John Ferguson, Sijia Liu, Chao Cui, Maria Romina Girotti, Gary Sibbet, Ellen B. Higgs, Morven K. Shuttleworth, Tom Hamilton, Paul Lorigan, Michael Weller, David F. Vincent, Owen J. Sansom, Margaret Frame, Peter Ten Dijke, Richard Marais, Gareth J. Inman (Lead / Corresponding author)

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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.

Original language	English
Pages (from-to)	81995-82012
Number of pages	18
Journal	Oncotarget
Volume	7
Issue number	50
Early online date	9 Nov 2016
DOIs	https://doi.org/10.18632/oncotarget.13226
Publication status	Published - 13 Dec 2016

Keywords

melanoma
BRAF
verurafenib
PLX-4720
TFG-beta

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Spender, L. C., Ferguson, G. J., Liu, S., Cui, C., Girotti, M. R., Sibbet, G., Higgs, E. B., Shuttleworth, M. K., Hamilton, T., Lorigan, P., Weller, M., Vincent, D. F., Sansom, O. J., Frame, M., Ten Dijke, P., Marais, R., & Inman, G. J. (2016). Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells. Oncotarget, 7(50), 81995-82012. https://doi.org/10.18632/oncotarget.13226

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

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-na{\"i}ve 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 = "melanoma, BRAF, verurafenib, PLX-4720, TFG-beta",

author = "Spender, {Lindsay C.} and Ferguson, {G. John} and Sijia Liu and Chao Cui and Girotti, {Maria Romina} and Gary Sibbet and Higgs, {Ellen B.} and Shuttleworth, {Morven K.} and Tom Hamilton and Paul Lorigan and Michael Weller and Vincent, {David F.} and Sansom, {Owen J.} and Margaret Frame and {Ten Dijke}, Peter and Richard Marais and Inman, {Gareth J.}",

note = "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.",

year = "2016",

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Spender, LC, Ferguson, GJ, Liu, S, Cui, C, Girotti, MR, Sibbet, G, Higgs, EB, Shuttleworth, MK, Hamilton, T, Lorigan, P, Weller, M, Vincent, DF, Sansom, OJ, Frame, M, Ten Dijke, P, Marais, R & Inman, GJ 2016, 'Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells', Oncotarget, vol. 7, no. 50, pp. 81995-82012. https://doi.org/10.18632/oncotarget.13226

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 -

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

Abstract

Keywords

UN SDGs

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