A1 Refereed original research article in a scientific journal
Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer
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.
Publisher: SPRINGERNATURE
Publication year: 2021
Journal: Nature Cancer
Journal name in source: NATURE CANCER
Journal acronym: NAT CANCER
Volume: 2
First page : 978
Last page: 993
Number of pages: 31
eISSN: 2662-1347
DOI: https://doi.org/10.1038/s43018-021-00237-1
Web address : https://rdcu.be/cyGrE
Self-archived copy’s web address: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562569/
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 antitumor 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 antitumor 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 patients with advanced prostate cancer and be an effective treatment strategy alone or in combination with immunotherapies.Chinnaiyan and colleagues perform a high-throughput compound screen and identify PIKfyve inhibition as a therapeutic strategy to enhance immune checkpoint blockade responses in advanced prostate cancer.
