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

Abstract

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 CXCL10 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.

• Authors: Yuanyuan Qiao, Jae Eun Choi, Jean C Tien, Stephanie A Simko, Thekkelnaycke Rajendiran, Josh N Vo, Andrew D Delekta, Lisha Wang, Lanbo Xiao, Nathan B Hodge, Parth Desai, Sergio Mendoza, Kristin Juckette, Alice Xu, Tanu Soni, Fengyun Su, Rui Wang, Xuhong Cao, Jiali Yu, Ilona Kryczek, Xiao-Ming Wang, Xiaoju Wang, Javed Siddiqui, Zhen Wang, Amélie Bernard, Ester Fernandez-Salas, Nora M Navone, Stephanie J Ellison, Ke Ding, Eeva-Liisa Eskelinen, Elisabeth I Heath, Daniel J Klionsky, Weiping Zou, Arul M Chinnaiyan
• Journal: Nature cancer (Nat Cancer) Vol. 2 Pg. 978-993 (09 2021) ISSN: 2662-1347 [Electronic] England
• PMID: 34738088 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immune Checkpoint Inhibitors
• PIKFYVE protein, human

Topics

• Autophagy
• Humans
• Immune Checkpoint Inhibitors
• Immunotherapy (methods)
• Male
• Phosphatidylinositol 3-Kinases (pharmacology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• Tumor Microenvironment