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

L C Spender; G. John Ferguson; Sijia Liu; Maria 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.

L C Spender, G. John Ferguson, Sijia Liu, Maria 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

Research output: Contribution to journal › Article › peer-review

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
Journal	Oncotarget
Early online date	9 Nov 2016
DOIs	https://doi.org/10.18632/oncotarget.13226
Publication status	Published - 2016

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Spender, L. C., Ferguson, G. J., Liu, S., Girotti, M., 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. https://doi.org/10.18632/oncotarget.13226

@article{49b079efaa67410f979182342ee73364,

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.",

author = "Spender, {L C} and Ferguson, {G. John} and Sijia Liu and Maria Girotti 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}",

year = "2016",

doi = "10.18632/oncotarget.13226",

language = "English",

journal = "Oncotarget",

issn = "1949-2553",

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Spender, LC, Ferguson, GJ, Liu, S, Girotti, M, 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. https://doi.org/10.18632/oncotarget.13226

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

AU - Spender, L C

AU - Ferguson, G. John

AU - Liu, Sijia

AU - Girotti, Maria

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

PY - 2016

Y1 - 2016

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.

U2 - 10.18632/oncotarget.13226

DO - 10.18632/oncotarget.13226

M3 - Article

SN - 1949-2553

JO - Oncotarget

JF - Oncotarget

ER -

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

Abstract

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