Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer

• Published in: Nature cancer Vol. 2; no. 9; pp. 978 - 993
• Main Authors: Qiao, Yuanyuan, Choi, Jae Eun, Tien, Jean C, Simko, Stephanie A, Rajendiran, Thekkelnaycke, Vo, Josh N, Delekta, Andrew D, Wang, Lisha, Xiao, Lanbo, Hodge, Nathan B, Desai, Parth, Mendoza, Sergio, Juckette, Kristin, Xu, Alice, Soni, Tanu, Su, Fengyun, Wang, Rui, Cao, Xuhong, Yu, Jiali, Kryczek, Ilona, Wang, Xiao-Ming, Wang, Xiaoju, Siddiqui, Javed, Wang, Zhen, Bernard, Amélie, Fernandez-Salas, Ester, Navone, Nora M, Ellison, Stephanie J, Ding, Ke, Eskelinen, Eeva-Liisa, Heath, Elisabeth I, Klionsky, Daniel J, Zou, Weiping, Chinnaiyan, Arul M
• Format: Journal Article
• Language: English
• Published: England Nature Research 01-09-2021
• Subjects: Autophagy; Humans; Immune Checkpoint Inhibitors; Immunotherapy - methods; Life Sciences; Male; Phosphatidylinositol 3-Kinases - pharmacology; Prostatic Neoplasms, Castration-Resistant - drug therapy; Tumor Microenvironment
• ISSN: 2662-1347; 2662-1347
• DOI: 10.1038/s43018-021-00237-1

Multi-tyrosine kinase inhibitors (MTKIs) have thus far had limited success in the treatment of castration-resistant prostate cancer (CRPC). Here, we report a phase I-cleared orally bioavailable MTKI, ESK981, with a novel autophagy inhibitory property that decreased tumor growth in diverse preclinical models of CRPC. The anti-tumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated
expression through the interferon gamma pathway and promoted functional T cell infiltration, which resulted in enhanced therapeutic response to immune checkpoint blockade. Mechanistically, we identify the lipid kinase PIKfyve as the direct target of ESK981. PIKfyve-knockdown recapitulated ESK981's anti-tumor activity and enhanced the therapeutic benefit of immune checkpoint blockade. Our study reveals that targeting PIKfyve via ESK981 turns tumors from cold into hot through inhibition of autophagy, which may prime the tumor immune microenvironment in advanced prostate cancer patients and be an effective treatment strategy alone or in combination with immunotherapies.