Repurposing colforsin daropate to treat MYC-driven high-grade serous ovarian carcinomas

Menée in vitro et à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence l'intérêt de la colforsine daropate pour traiter un carcinome ovarien séreux de haut grade induit par MYC

Résumé en anglais

High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers for women, with a low survival rate, no early detection biomarkers, a high rate of recurrence, and few therapeutic options. Forskolin, an activator of cyclic AMP signaling, has several anticancer activities, including against HGSOC, but has limited use in vivo. Its water-soluble derivative, colforsin daropate, has the same mechanism of action as forskolin and is used to treat acute heart failure. Here, we investigated the potential of colforsin daropate as a treatment for HGSOC. We found that colforsin daropate induced cell cycle arrest and apoptosis in cultured HGSOC cells and spheroids but had negligible cytotoxicity in immortalized, nontumorigenic fallopian tube secretory cells and ovarian surface epithelial cells. Colforsin daropate also prevented HGSOC cells from invading ovarian surface epithelial cell layers in culture. In vivo, colforsin daropate reduced tumor growth, synergized with cisplatin (a standard chemotherapy in ovarian cancer care), and improved host survival in subcutaneous and intraperitoneal xenograft models. These antitumor effects of colforsin daropate were mediated in part by its reduction in the abundance and transcriptional activity of the oncoprotein c-MYC, which is often increased in HGSOC. Our findings demonstrate that colforsin daropate may be a promising therapeutic that could be combined with conventional therapies to treat HGSOC. A drug that treats acute heart failure may also be used to treat an aggressive subtype of ovarian cancer. High-grade serous ovarian cancer (HGSOC) is aggressive and lacks durably effective treatments. Forskolin can suppress cancer cell proliferation but cannot be used clinically. Knarr et al. found that colforsin daropate, a forskolin derivative, specifically induced cell death in HGSOC cells but not normal fallopian or ovarian cells and inhibited HGSOC invasion in part by attenuating MYC signaling. Colforsin daropate synergized with cisplatin, a standard ovarian cancer chemotherapeutic, and resensitized cisplatin-resistant tumors in mice. Because colforsin daropate is already approved to treat acute heart failure, it could potentially be repurposed to treat HGSOC. —Leslie K. Ferrarelli