Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma

Cancers
Laurie SignettiIsabelle Mus-Veteau

Abstract

Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAFV600E melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that PAH is a highly promising lead for the treatment of vemurafenib resistant BRAFV600E melanoma.

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Citations

Feb 2, 2021·Physical Chemistry Chemical Physics : PCCP·Sandra KovachkaPaolo Ruggerone
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nelly DurandIsabelle Mus-Veteau

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Methods Mentioned

BETA
transfection
microscale thermophoresis
fluorescence microscopy
Xenografted
xenografts
xenograft
column chromatography
NMR
protein assay

Software Mentioned

Prism
R package curatedTCGAData
ANTECHAMBER Amber
ProteinsPlus
PoseView
USCF Chimera Predock Toolkit
GraphPad Prism
MuTect2
R package
GraphPad

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