Dual inhibition of mTOR and HSP90 enhances cisplatin efficacy and overcomes resistance in ovarian cancer

Epithelial ovarian cancer (EOC) represents the most lethal gynecological disease, with a 5-year relative survival rate of 46% after the diagnosis. Standard treatment includes surgery followed by platinum (Pt)-based chemotherapy. However, Pt-resistance frequently occurs and strongly impact on the survival of EOC patients for whom we still do not have valid therapeutic options. By using a proteomic approach, we previously demonstrated a potential role of HSP90 in the mechanism of resistance in vitro, ex vivo e partially in vivo. To further investigate in depth the mechanism by which EOC cells acquired Pt-resistance, we used a quantitative phosphoproteomics approach followed by enrichment functional analysis. Here, we identified 542 differentially expressed phosphoproteins in Pt-resistant compared to parental cells identifying mTOR and HSF1 as the most enriched pathways. The up-regulation of the phosphorylated form of PDK1, AKT, mTOR, and RPS6 was observed in Pt-resistant compared to parental cells. Moreover, we also demonstrated the up-regulation of the activity of HSF1 along with the elevation crucial components of the chaperone complex machinery HSP90, HSP70 and HSP40. Since mTOR is an attractive target for therapeutic intervention because of its key role in the crosstalk of various signaling pathways, we propose a novel therapeutic strategy based on the pharmacologic inhibition of HSP90 and mTOR able to further potentiate the Pt-based chemotherapy. Accordingly, the combination of ganetespib (an HSP90 inhibitor) and temsirolimus (a FDA approved-mTOR inhibitor) with cisplatin synergistically reduced colony formation and microtissues cell growth in vitro by increasing DNA-damage and apoptosis and in vivo enhancing mouse survival. Mechanistically, the triple combination treatment, impaired the proteins involved in mTOR signaling and HSF1 transactivation. Notably, all these data were confirmed also in Pt-resistant Non Small Cell Lung Cancer models. Collectively, our findings identify a promising new antitumor strategy for the treatment of Pt-resistance in cancer patients.