Hsp90beta选择性抑制与PARPi在同源重组修复功能正常的卵巢癌中的合成致死作用

A significant unmet need exists for cancer patients who are ineligible for PARP inhibitor (PARPi) therapy due to their genetic makeup and/or acquired PARPi resistance. Synthetic lethality occurs when PARP inhibition is combined with an agent that disrupts the DNA double-strand breakage (DSB) repair mechanisms, causing apoptosis and cell death. Inhibition of the Heat Shock Protein 90 (Hsp90) represents an ideal candidate to disrupt DSB repair and induce synthetic lethality with PARP inhibitors, as multiple Hsp90 client proteins are involved in the DSB repair pathways including homologous recombination (HR) repair pathway. Unfortunately, no Hsp90 inhibitor is FDA approved for use due to dose-limiting and on-target toxicities. Hsp90 exists as four isoforms in the cell, Hsp90alpha, Hsp90beta, Grp94 and Trap-1. The cytosolic isoforms Hsp90alpha and Hsp90beta significantly contribute to cancer growth and progression. Interestingly, inhibition of Hsp90alpha by non-selective (pan-Hsp90) inhibitors can cause cardiac and ocular toxicities. Additionally, inhibitor binding to the inducible isoform, Hsp90alpha, can also contribute to dosing-challenges associated with previously evaluated pan-Hsp90 inhibitors. Therefore, Hsp90beta-selective inhibition has been proposed as safer alternative to pan-Hsp90 inhibition for cancer treatment. This presentation will contain results from mechanistic, efficacy and safety studies of the orally bioavailable and efficacious Hsp90beta-selective inhibitor in combination with a PARP inhibitor.