Isabelle Mus-Veteau

IPMC, CNRS, University Côte d'Azur

Title: Drug Efflux Activity of Ptch1 and Chemotherapy Resistance

---

Biography

Dr Isabelle Mus-Veteau (PhD) is a CNRS Research director. She heads a group in Franco-Luton’s team at IPMC (Sophia Antipolis). She has made seminal contributions to the understanding of the biological properties of  the  human Shh receptor  Ptch1.  She was the  first  to  demonstrate  that  Ptch1 transports  cholesterol  and chemotherapeutics,  and  to  identify  inhibitors  of  Ptch1  drug  efflux activity  (patents  PCT/EP2015/074771; PCT/EP17/306544.2  1462, EP193006057.1-1110).

Abstract

We demonstrated that the Hedgehog receptor Ptch1, which is overexpressed in many recurrent and metastatic cancers, pumps chemotherapeutic agents such as doxorubicin out of cancer cells using the proton motive force. We discovered small molecules which inhibit the doxorubicin efflux activity of Ptch1 and enhance its cytotoxicity on adrenocortical carcinoma and melanoma cells which endogenously overexpress Ptch1, and thereby mitigates the resistance of these cancer cells to doxorubicin. Our recent results show that these Ptch1 drug efflux inhibitors also enhance the efficacy of the targeted therapy vemurafenib against BRAFV600E melanoma cells resistant to the treatment. The clinical responses to vemurafenib are heterogeneous, and almost all patients who experience an initial response ultimately acquire resistance that allows disease progression. Our results suggest that the use of inhibitors of Ptch1 drug efflux in combination with vemurafenib could be a promising therapeutic option to improve vemurafenib efficiency against treatment resistant BRAF mutated melanomas.