Session 3:  Cancer therapeutic innovations

Ptch1 drug efflux inhibition: a promising strategy to overcome chemotherapy resistance of cancer cells

Purpose - 90% of deaths from cancer are the result of recurrence or metastasis due to tumor cell resistance to anti-cancer treatments. The presence of proteins capable to efflux chemotherapeutic agents out of tumor cells is one of the major mechanisms of chemotherapy resistance and the main cause of therapeutic failures. Some multidrug transport proteins (known as multidrug resistance (MDR) proteins or drug efflux pumps) from the ABC transporters family have been identified as responsible for chemotherapy resistance. Numerous inhibitors of these ABC transporters have been developed but none of these molecules has obtained marketing authorization. These molecules are either ineffective, or toxic given the importance of these transporters for homeostasis of healthy cells. The need for drugs capable of combating resistance to chemotherapies and targeted therapies via inhibition of the MDR transporters involved in treatment resistance is therefore as strong as ever.

Experimental Design - TCGA data analysis, cancer cell culture, Ptch1 silencing, doxorubicin efflux, cell viability, wound-healing, microscale thermophoresis, in silico docking, cancer cells xenografts in Chick Eggs and mice.

Results - Hedgehog signaling is aberrantly activated, and the Hedgehog receptor Ptch1 is overexpressed in many recurrent and metastatic cancers. We showed that Ptch1 pumps chemotherapeutic agents such as doxorubicin out of cancer cells using the proton motive force and contributes to chemotherapy resistance of several cancer cell types, and that cells overexpressing Ptch1 at their plasma membrane have cancer stem cell properties.  We identified a small molecule which inhibits the doxorubicin efflux activity of Ptch1 and enhances its cytotoxicity in different cancer cell lines endogenously overexpressing Ptch1, and thereby mitigates the resistance of these cancer cells to doxorubicin. We also showed that this Ptch1 drug efflux inhibitor enhances the efficacy of kinase inhibitors such as vemurafenib against melanoma cells resistant to the treatment in cellulo and in vivo on xenografts in mice.

Conclusion - Our data suggest that the use of an inhibitor of Ptch1 drug efflux in combination with chemotherapy could be a promising therapeutic option to improve treatment efficacy against cancer cells expressing Ptch1, reduce relapse and increase patient survival.

References

- Feliz Morel et al 2022

- Kovachka et al 2022

- Kovachka et al 2021

- Signetti et al 2020