Pimitespib, an HSP90 Inhibitor, Enhances the Efficacy of PARP Inhibitors in PARP Inhibitor-Insensitive Breast Cancer Cells

Abstract

Heat shock protein 90 (HSP90) plays a crucial role in the maintenance of protein homeostasis in cancer cells. Inhibition of HSP90 is anticipated to exert anticancer activities by reducing levels of HSP90 client proteins. Pimitespib (TAS-116) has emerged as a potent ATP-competitive inhibitor of both HSP90α and β, demonstrating favorable therapeutic properties in preclinical models. Notably, pimitespib is the first HSP90 inhibitor approved for the treatment of advanced gastrointestinal stromal tumors in Japan. Poly(ADP-ribose) polymerase (PARP) inhibitors target cancers susceptible to the homologous recombination (HR) pathway and are used for treating various types of tumors, particularly those harboring defects in HR repair pathways within DNA damage repair (DDR) such as mutations in breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively). However, PARP inhibitors have shown limited efficacy in HR-proficient tumors, and the development of resistance to PARP inhibitors via restoration of DDR systems poses a significant challenge. In this study, we explored the potential of pimitespib to enhance PARP inhibitor activity. In PARP inhibitor-insensitive breast cancer cell lines, pimitespib impaired HR pathway function by promoting the proteasome-mediated degradation of proteins involved in HR, such as BRCA1, BRCA2, and Rad51 homologous 1 (RAD51). Consequently, pimitespib enhanced antitumor activity and DNA damage induced by PARP inhibitors in vitro. In human breast cancer xenograft mouse models, pimitespib downregulated RAD51 proteins and augmented the antitumor effects of PARP inhibitors. These findings highlight the potential of pimitespib as a therapeutic agent in combination with PARP inhibitors to treat PARP inhibitor-insensitive cancers.