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Volume 12
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10.3390/cancers12061500
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Article

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

by
Laurie Signetti
1,
Nelli Elizarov
2,
Méliné Simsir
1,
Agnès Paquet
1,
Dominique Douguet
1,
Fabien Labbal
1,
Delphine Debayle
1,
Audrey Di Giorgio
2,
Valérie Biou
3,
Christophe Girard
4,
Maria Duca
2,
Lionel Bretillon
5,
Corine Bertolotto
4,
Bernard Verrier
6,
Stéphane Azoulay
2,* and
Isabelle Mus-Veteau
1,*
1
Université Côte d’Azur, CNRS, IPMC, 660 Route des Lucioles, 06560 Valobonne, France
2
Université Côte d’Azur, CNRS, ICN, 28 Avenue Valrose, 06108 Nice, CEDEX 2, France
3
CNRS, IBPC, Sorbonne Paris Cité, Laboratoire de Biologie Physico-Chimique des Protéines Membranaires, Institut de Biologie Physico-Chimique, University Paris Diderot, 13 rue Pierre et Marie Curie, 75005 Paris, France
4
Université Côte d’Azur, INSERM, CNRS, C3M, Bâtiment Universitaire ARCHIMED 151 Route Saint Antoine de Ginestière BP 2 3194, 06204 Nice, CEDEX 3, France
5
Centre des Sciences du Goût et de l’Alimentation, Université Bourgogne Franche-Comté CNRS, INRA, SSGA, AgroSup Dijon, F-21000 Dijon, France
6
Adjuvatis SAS, IBCP, 7 Passage du Vercors—69007 Lyon, France
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(6), 1500; https://doi.org/10.3390/cancers12061500
Submission received: 5 May 2020 / Revised: 3 June 2020 / Accepted: 5 June 2020 / Published: 9 June 2020
(This article belongs to the Special Issue The Role of Drug Resistance-Associated Proteins in Cancer: from Conventional Anticancer Drugs to Targeting Drugs)
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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.
Keywords: Patched; melanoma; vemurafenib; chemotherapy resistance: drug efflux; new therapeutic lead Patched; melanoma; vemurafenib; chemotherapy resistance: drug efflux; new therapeutic lead

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MDPI and ACS Style

Signetti, L.; Elizarov, N.; Simsir, M.; Paquet, A.; Douguet, D.; Labbal, F.; Debayle, D.; Di Giorgio, A.; Biou, V.; Girard, C.; et al. Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma. Cancers 2020, 12, 1500. https://doi.org/10.3390/cancers12061500

AMA Style

Signetti L, Elizarov N, Simsir M, Paquet A, Douguet D, Labbal F, Debayle D, Di Giorgio A, Biou V, Girard C, et al. Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma. Cancers. 2020; 12(6):1500. https://doi.org/10.3390/cancers12061500

Chicago/Turabian Style

Signetti, Laurie, Nelli Elizarov, Méliné Simsir, Agnès Paquet, Dominique Douguet, Fabien Labbal, Delphine Debayle, Audrey Di Giorgio, Valérie Biou, Christophe Girard, and et al. 2020. "Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma" Cancers 12, no. 6: 1500. https://doi.org/10.3390/cancers12061500

APA Style

Signetti, L., Elizarov, N., Simsir, M., Paquet, A., Douguet, D., Labbal, F., Debayle, D., Di Giorgio, A., Biou, V., Girard, C., Duca, M., Bretillon, L., Bertolotto, C., Verrier, B., Azoulay, S., & Mus-Veteau, I. (2020). Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma. Cancers, 12(6), 1500. https://doi.org/10.3390/cancers12061500

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