New anti-cancer molecules targeting HSPA5/BIP to induce endoplasmic reticulum stress, autophagy and apoptosis.

Treatment of melanoma has significantly advanced over the last decade, with the development of targeted therapies against the MAPK pathway and immunotherapies to reactivate antitumor immunity. Unfortunately, currently more than 50% of patients are in treatment failure. Thus, identification of new common cellular vulnerability among melanoma cells is an urgent need and will help in the discovery of more efficient treatments against melanoma. We have focused our study on protein processing and have identified a new compound, HA15, targeting HSPA5/BiP, the master regulator of the unfolded protein response (UPR). By inhibiting HSPA5 specifically, our molecule increases the UPR and leads to the death of cancer cells by concomitant induction of autophagy and apoptosis, an effect seen both in vitro and in vivo. Our study provides compelling evidence to support the idea that endoplasmic reticulum (ER) stress inducers could be useful as a new therapeutic approach in melanoma treatment.