Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer
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 preclinica...
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| Veröffentlicht in: | Nature cancer 2021-09, Vol.2 (9), p.978-993 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1038/s43018-021-00237-1 |
| format | Article |
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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.</description><identifier>ISSN: 2662-1347</identifier><identifier>EISSN: 2662-1347</identifier><identifier>DOI: 10.1038/s43018-021-00237-1</identifier><identifier>PMID: 34738088</identifier><language>eng</language><publisher>England: Nature Research</publisher><subject>Autophagy ; Humans ; Immune Checkpoint Inhibitors ; Immunotherapy - methods ; Life Sciences ; Male ; Phosphatidylinositol 3-Kinases - pharmacology ; Prostatic Neoplasms, Castration-Resistant - drug therapy ; Tumor Microenvironment</subject><ispartof>Nature cancer, 2021-09, Vol.2 (9), p.978-993</ispartof><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c436t-f9d9a36ebdd86710f291c49638859d5aa2df89752aac87a3672fb6559e6850973</citedby><cites>FETCH-LOGICAL-c436t-f9d9a36ebdd86710f291c49638859d5aa2df89752aac87a3672fb6559e6850973</cites><orcidid>0000-0002-3130-2533 ; 0000-0003-1381-2713 ; 0000-0001-9282-3415 ; 0000-0003-0006-7785 ; 0000-0002-7828-8118 ; 0000-0001-7952-3549 ; 0000-0001-7073-2440</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34738088$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03440254$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Qiao, Yuanyuan</creatorcontrib><creatorcontrib>Choi, Jae Eun</creatorcontrib><creatorcontrib>Tien, Jean C</creatorcontrib><creatorcontrib>Simko, Stephanie A</creatorcontrib><creatorcontrib>Rajendiran, Thekkelnaycke</creatorcontrib><creatorcontrib>Vo, Josh N</creatorcontrib><creatorcontrib>Delekta, Andrew D</creatorcontrib><creatorcontrib>Wang, Lisha</creatorcontrib><creatorcontrib>Xiao, Lanbo</creatorcontrib><creatorcontrib>Hodge, Nathan B</creatorcontrib><creatorcontrib>Desai, Parth</creatorcontrib><creatorcontrib>Mendoza, Sergio</creatorcontrib><creatorcontrib>Juckette, Kristin</creatorcontrib><creatorcontrib>Xu, Alice</creatorcontrib><creatorcontrib>Soni, Tanu</creatorcontrib><creatorcontrib>Su, Fengyun</creatorcontrib><creatorcontrib>Wang, Rui</creatorcontrib><creatorcontrib>Cao, Xuhong</creatorcontrib><creatorcontrib>Yu, Jiali</creatorcontrib><creatorcontrib>Kryczek, Ilona</creatorcontrib><creatorcontrib>Wang, Xiao-Ming</creatorcontrib><creatorcontrib>Wang, Xiaoju</creatorcontrib><creatorcontrib>Siddiqui, Javed</creatorcontrib><creatorcontrib>Wang, Zhen</creatorcontrib><creatorcontrib>Bernard, Amélie</creatorcontrib><creatorcontrib>Fernandez-Salas, Ester</creatorcontrib><creatorcontrib>Navone, Nora M</creatorcontrib><creatorcontrib>Ellison, Stephanie J</creatorcontrib><creatorcontrib>Ding, Ke</creatorcontrib><creatorcontrib>Eskelinen, Eeva-Liisa</creatorcontrib><creatorcontrib>Heath, Elisabeth I</creatorcontrib><creatorcontrib>Klionsky, Daniel J</creatorcontrib><creatorcontrib>Zou, Weiping</creatorcontrib><creatorcontrib>Chinnaiyan, Arul M</creatorcontrib><title>Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer</title><title>Nature cancer</title><addtitle>Nat Cancer</addtitle><description>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.</description><subject>Autophagy</subject><subject>Humans</subject><subject>Immune Checkpoint Inhibitors</subject><subject>Immunotherapy - methods</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Phosphatidylinositol 3-Kinases - pharmacology</subject><subject>Prostatic Neoplasms, Castration-Resistant - drug therapy</subject><subject>Tumor Microenvironment</subject><issn>2662-1347</issn><issn>2662-1347</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU9v1DAQxSMEolXpF-CAfIRDwH9ix74gLatCV6zECpWz5TiTjWlih9hZab89XrZUhZOtmfeePfMritcEvyeYyQ-xYpjIElNSYkxZXZJnxSUVgpaEVfXzJ_eL4jrGnzirOCFcyZfFRa4yiaW8LMJqSWHqzf6INr53jUsueNQc0Z2Z95Cc36Pd5mt3PADahQQ-OZMgou8Qp-AjoBTQZhwXD2jdg72fgvMJfRqCvTctIOfRbg4xZQ9aG29hflW86MwQ4frhvCp-fL65W9-W229fNuvVtrQVE6nsVKsME9C0rRQ1wR1VxFZKMCm5arkxtO2kqjk1xso6K2vaNYJzBUJyrGp2VXw8505LM0Jr889nM-hpdqOZjzoYp__teNfrfThoyQXlQuWAd-eA_j_b7WqrTzXMqiqvtDqQrH378Ngcfi0Qkx5dtDAMxkNYoqZcVVTRWsgspWepzXuJM3SP2QTrE1h9BqszWP0HrD7lv3k6zKPlL0b2G3Ceny8</recordid><startdate>20210901</startdate><enddate>20210901</enddate><creator>Qiao, Yuanyuan</creator><creator>Choi, Jae Eun</creator><creator>Tien, Jean C</creator><creator>Simko, Stephanie A</creator><creator>Rajendiran, Thekkelnaycke</creator><creator>Vo, Josh N</creator><creator>Delekta, Andrew D</creator><creator>Wang, Lisha</creator><creator>Xiao, Lanbo</creator><creator>Hodge, Nathan B</creator><creator>Desai, Parth</creator><creator>Mendoza, Sergio</creator><creator>Juckette, Kristin</creator><creator>Xu, Alice</creator><creator>Soni, Tanu</creator><creator>Su, Fengyun</creator><creator>Wang, Rui</creator><creator>Cao, Xuhong</creator><creator>Yu, Jiali</creator><creator>Kryczek, Ilona</creator><creator>Wang, Xiao-Ming</creator><creator>Wang, Xiaoju</creator><creator>Siddiqui, Javed</creator><creator>Wang, Zhen</creator><creator>Bernard, Amélie</creator><creator>Fernandez-Salas, Ester</creator><creator>Navone, Nora M</creator><creator>Ellison, Stephanie J</creator><creator>Ding, Ke</creator><creator>Eskelinen, Eeva-Liisa</creator><creator>Heath, Elisabeth I</creator><creator>Klionsky, Daniel J</creator><creator>Zou, Weiping</creator><creator>Chinnaiyan, Arul M</creator><general>Nature Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3130-2533</orcidid><orcidid>https://orcid.org/0000-0003-1381-2713</orcidid><orcidid>https://orcid.org/0000-0001-9282-3415</orcidid><orcidid>https://orcid.org/0000-0003-0006-7785</orcidid><orcidid>https://orcid.org/0000-0002-7828-8118</orcidid><orcidid>https://orcid.org/0000-0001-7952-3549</orcidid><orcidid>https://orcid.org/0000-0001-7073-2440</orcidid></search><sort><creationdate>20210901</creationdate><title>Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c436t-f9d9a36ebdd86710f291c49638859d5aa2df89752aac87a3672fb6559e6850973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Autophagy</topic><topic>Humans</topic><topic>Immune Checkpoint Inhibitors</topic><topic>Immunotherapy - methods</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Phosphatidylinositol 3-Kinases - pharmacology</topic><topic>Prostatic Neoplasms, Castration-Resistant - drug therapy</topic><topic>Tumor Microenvironment</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Qiao, Yuanyuan</creatorcontrib><creatorcontrib>Choi, Jae Eun</creatorcontrib><creatorcontrib>Tien, Jean C</creatorcontrib><creatorcontrib>Simko, Stephanie A</creatorcontrib><creatorcontrib>Rajendiran, Thekkelnaycke</creatorcontrib><creatorcontrib>Vo, Josh N</creatorcontrib><creatorcontrib>Delekta, Andrew D</creatorcontrib><creatorcontrib>Wang, Lisha</creatorcontrib><creatorcontrib>Xiao, Lanbo</creatorcontrib><creatorcontrib>Hodge, Nathan B</creatorcontrib><creatorcontrib>Desai, Parth</creatorcontrib><creatorcontrib>Mendoza, Sergio</creatorcontrib><creatorcontrib>Juckette, Kristin</creatorcontrib><creatorcontrib>Xu, Alice</creatorcontrib><creatorcontrib>Soni, Tanu</creatorcontrib><creatorcontrib>Su, Fengyun</creatorcontrib><creatorcontrib>Wang, Rui</creatorcontrib><creatorcontrib>Cao, Xuhong</creatorcontrib><creatorcontrib>Yu, Jiali</creatorcontrib><creatorcontrib>Kryczek, Ilona</creatorcontrib><creatorcontrib>Wang, Xiao-Ming</creatorcontrib><creatorcontrib>Wang, Xiaoju</creatorcontrib><creatorcontrib>Siddiqui, Javed</creatorcontrib><creatorcontrib>Wang, Zhen</creatorcontrib><creatorcontrib>Bernard, Amélie</creatorcontrib><creatorcontrib>Fernandez-Salas, Ester</creatorcontrib><creatorcontrib>Navone, Nora M</creatorcontrib><creatorcontrib>Ellison, Stephanie J</creatorcontrib><creatorcontrib>Ding, Ke</creatorcontrib><creatorcontrib>Eskelinen, Eeva-Liisa</creatorcontrib><creatorcontrib>Heath, Elisabeth I</creatorcontrib><creatorcontrib>Klionsky, Daniel J</creatorcontrib><creatorcontrib>Zou, Weiping</creatorcontrib><creatorcontrib>Chinnaiyan, Arul M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Qiao, Yuanyuan</au><au>Choi, Jae Eun</au><au>Tien, Jean C</au><au>Simko, Stephanie A</au><au>Rajendiran, Thekkelnaycke</au><au>Vo, Josh N</au><au>Delekta, Andrew D</au><au>Wang, Lisha</au><au>Xiao, Lanbo</au><au>Hodge, Nathan B</au><au>Desai, Parth</au><au>Mendoza, Sergio</au><au>Juckette, Kristin</au><au>Xu, Alice</au><au>Soni, Tanu</au><au>Su, Fengyun</au><au>Wang, Rui</au><au>Cao, Xuhong</au><au>Yu, Jiali</au><au>Kryczek, Ilona</au><au>Wang, Xiao-Ming</au><au>Wang, Xiaoju</au><au>Siddiqui, Javed</au><au>Wang, Zhen</au><au>Bernard, Amélie</au><au>Fernandez-Salas, Ester</au><au>Navone, Nora M</au><au>Ellison, Stephanie J</au><au>Ding, Ke</au><au>Eskelinen, Eeva-Liisa</au><au>Heath, Elisabeth I</au><au>Klionsky, Daniel J</au><au>Zou, Weiping</au><au>Chinnaiyan, Arul M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer</atitle><jtitle>Nature cancer</jtitle><addtitle>Nat Cancer</addtitle><date>2021-09-01</date><risdate>2021</risdate><volume>2</volume><issue>9</issue><spage>978</spage><epage>993</epage><pages>978-993</pages><issn>2662-1347</issn><eissn>2662-1347</eissn><abstract>Multi-tyrosine kinase inhibitors (MTKIs) have thus far had limited success in the treatment of castration-resistant prostate cancer (CRPC). 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| subjects | Autophagy Humans Immune Checkpoint Inhibitors Immunotherapy - methods Life Sciences Male Phosphatidylinositol 3-Kinases - pharmacology Prostatic Neoplasms, Castration-Resistant - drug therapy Tumor Microenvironment |
| title | Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer |
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