Abstract 1339: Development of a novel autophagy-inducing multikinase inhibitor for the treatment of castration-resistant prostate cancer

Abstract

Abstract Inhibition of the androgen axis has revolutionized the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC continues to be a leading cause of cancer-related deaths in men. Here, we characterized a phase I-cleared multikinase inhibitor, ESK981, in prostate cancer preclinical models. ESK981 was markedly more potent in vitro than other kinase inhibitors, including cabozantinib and crizotinib, that have been evaluated clinically in prostate cancer. Surprisingly, we observed that ESK981 was a potent inducer of cellular vacuolization that was associated with an autophagic response. ESK981-induced autophagy could be blocked by either the depletion of the autophagy vesicle formation gene, atg5, or by autophagy inhibitors such as bafilomycin. ESK981 was further shown to induce autophagy in yeast, which is an evolutionarily conserved core cellular pathway. Moreover, ESK981 triggered prostate cancer cells to release chemokines such as CXCL10 into the cell secretome, thus suggesting that ESK981 may stimulate immune surveillance while exerting its tumor inhibitory effect. Together, ESK981 is a novel and potent autophagy-inducing multikinase inhibitor that effectively inhibits CRPC growth through the activation of the autophagic cascade. Citation Format: Yuanyuan Qiao. Development of a novel autophagy-inducing multikinase inhibitor for the treatment of castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1339.