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Artículo

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

Spender, Lindsay C.; Ferguson, John; Liu, Sijia; Cui, Chao; Girotti, Maria RominaIcon ; Sibbet, Gary; Higgs, Ellen; Shuttleworth, Morven K.; Hamilton, Tom; Lorigan, Paul; Weller, Michael; Vincent, David F.; Sansom, Owen J.; Frame, Margaret; Dijke, Peter ten; Marais, Richard; Inman, Gareth J.
Fecha de publicación: 09/11/2016
Editorial: Impact journals
Revista: Oncotarget
ISSN: 1949-2553
e-ISSN: 1949-2553
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Bioquímica y Biología Molecular

Resumen

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.
Palabras clave: Melanoma , Resistance , Tgfb , Braf , Vemurafenib , Plx 4720 , Tgf Beta
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution 2.5 Unported (CC BY 2.5)
Identificadores
URI: http://hdl.handle.net/11336/24320
URL: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=artic
DOI: http://dx.doi.org/10.18632/oncotarget.13226
URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347669/
Colecciones
Articulos(IBYME)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Citación
Spender, Lindsay C.; Ferguson, John; Liu, Sijia; Cui, Chao; Girotti, Maria Romina; et al.; Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells; Impact journals; Oncotarget; 7; 50; 9-11-2016; 81995-82012
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