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Mutational activation of BRAF confers sensitivity to transforming growth factor
beta inhibitors in human cancer cells
#MMPMID27835901
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
; Dijke PT
; Marais R
; Inman GJ
Oncotarget
2016[Dec]; 7
(50
): 81995-82012
PMID27835901
show ga
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.
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