1. Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer
- Author
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Jean C. Tien, Fengyun Su, Jiali Yu, Nathan B. Hodge, Eeva-Liisa Eskelinen, Parth Desai, Ilona Kryczek, Jae Eun Choi, Xiaoming Wang, Xiaoju Wang, Arul M. Chinnaiyan, Ester Fernandez-Salas, Yuanyuan Qiao, Thekkelnaycke M. Rajendiran, Sergio Mendoza, Xuhong Cao, Alice Xu, Stephanie J. Ellison, Lanbo Xiao, Lisha Wang, Weiping Zou, Amélie Bernard, Zhen Wang, Rui Wang, Daniel J. Klionsky, Ke Ding, Tanu Soni, Elisabeth I. Heath, Josh N. Vo, Javed Siddiqui, Andrew D. Delekta, Nora M. Navone, Stephanie A. Simko, Kristin M. Juckette, Laboratoire de Biogenèse Membranaire, CNRS UMR 5200, Université de Bordeaux, INRA Bordeaux Aquitaine, Villenave d'Ornon, France., Life Sciences Institute [Ann Arbor, MI, USA], University of Michigan [Ann Arbor], and University of Michigan System-University of Michigan System
- Subjects
Male ,Cancer Research ,[SDV]Life Sciences [q-bio] ,Article ,03 medical and health sciences ,PIKFYVE ,Prostate cancer ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Autophagy ,Tumor Microenvironment ,Humans ,Interferon gamma ,Immune Checkpoint Inhibitors ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,Kinase ,business.industry ,medicine.disease ,Immune checkpoint ,3. Good health ,Blockade ,Prostatic Neoplasms, Castration-Resistant ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Immunotherapy ,business ,medicine.drug - 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.
- Published
- 2021