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Seminar

Tuesday, October 30th, 2018
14h30
Centre de Recherche - Paris - Amphithéâtre Antoine Lacassagne

Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency

One of the crucial challenges in the clinical management of cancer is resistance to chemotherapeutics. Multidrug resistance (MDR) has been intensively studied, and one of the most prominent mechanisms underlying MDR is overexpression of ATP-binding cassette (ABC) transporters. Despite research efforts to develop compounds that inhibit the efflux activity of ABC transporters and thereby increase classical chemotherapy efficacy, to date, the Food and Drug Administration (FDA) has not approved the use of any ABC transporter inhibitors due to toxicity issues. Hedgehog signaling is aberrantly activated in many cancers, and has been shown to be involved in chemotherapy resistance. We showed that the Hedgehog receptor Ptch1, which is over-expressed in many recurrent and metastatic cancers, is a multidrug transporter and it contributes to the efflux of chemotherapeutic agents such as doxorubicin, and to chemotherapy resistance. Remarkably, Ptch1 uses the proton motive force to efflux drugs, in contrast to ABC transporters, which use ATP hydrolysis. Indeed, the “reversed pH gradient” that characterizes cancer cells, allows Ptch1 to function as an efflux pump specifically in cancer cells. This makes Ptch1 a particularly attractive therapeutic target for cancers expressing Ptch1, such as lung, breast, prostate, ovary, colon, brain, adrenocortical carcinoma, and melanoma. Screening of chemical libraries allowed us to identify several molecules that are able to enhance the cytotoxic effect of different chemotherapeutic agents by inhibiting Ptch1 drug efflux activity in different cancer cell lines that endogenously over-express Ptch1. We performed in vivo proof of concept in mice where combining one of these compounds with doxorubicin prevented the development of xenografted adrenocortical carcinoma tumors more efficiently than doxorubicin alone, and without obvious undesirable side effects. Therefore, we propose that the use of a Ptch1 drug efflux inhibitor in combination with classical or targeted therapy could be a promising therapeutic option for Ptch1-expressing cancers.

Speaker(s)

Dr. Isabelle Mus-Veteau
Directrice de Recherche CNRS

Institut de Pharmacologie Moléculaire et Cellulaire, UMR-CNRS 7275 660, route des Lucioles, Sophia Antipolis, Valbonne, France

Hosted by

Dr. Ludger Johannes
Domain 4 - UMR 3666 / U1143 - Chemical Biology of Membranes and Therapeutic Delivery

Institut Curie

Invited by

Dr. Ludger Johannes
Domain 4 - UMR 3666 / U1143 - Chemical Biology of Membranes and Therapeutic Delivery

Institut Curie

Contact

M. Yannick Bono

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References:

Hasanovic, A. and Mus-Veteau, I. Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency. Cells 2018, 7(8), 107; https://doi.org/10.3390/cells7080107

Hasanovic A, Ruggiero C, Jung S, Rapa I, Signetti L, Ben Hadj M, Terzolo M, Beuschlein F, Volante M, Hantel C, Lalli E, Mus-Veteau I. Targeting the multidrug transporter Patched potentiates chemotherapy efficiency on adrenocortical carcinoma in vitro and in vivo. Int J Cancer. 2018 Jul 1;143(1):199-211. doi:10.1002/ijc.31296. Epub 2018 Feb 23. PubMed PMID: 29411361.

Fiorini L, Tribalat MA, Sauvard L, Cazareth J, Lalli E, Broutin I, Thomas OP, Mus-Veteau I. Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells. Oncotarget. 2015 Sep 8;6(26):22282-97. PubMed PMID: 26068979; PubMed

Central PMCID: PMC4673163.

Bidet M, Tomico A, Martin P, Guizouarn H, Mollat P, Mus-Veteau I. The Hedgehog receptor patched functions in multidrug transport and chemotherapy resistance. Mol Cancer Res. 2012 Nov;10(11):1496-508. doi: 10.1158/1541-7786.MCR-11-0578. Epub 2012 Jul 2. PubMed PMID: 22752092.