Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer

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

doi:10.1038/s43018-021-00237-1

Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer

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 KryczekXiao 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

Genitourinary Medical Oncology

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

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 antitumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated CXCL10 expression through the interferon-γ 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.

Original language	English (US)
Pages (from-to)	978-993
Number of pages	16
Journal	Nature Cancer
Volume	2
Issue number	9
DOIs	https://doi.org/10.1038/s43018-021-00237-1
State	Published - Sep 2021

ASJC Scopus subject areas

Oncology
Cancer Research
General Medicine

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Qiao, Y., Choi, J. E., Tien, J. C., Simko, S. A., Rajendiran, T., Vo, J. N., Delekta, A. D., Wang, L., Xiao, L., Hodge, N. B., Desai, P., Mendoza, S., Juckette, K., Xu, A., Soni, T., Su, F., Wang, R., Cao, X., Yu, J., ... Chinnaiyan, A. M. (2021). Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer. Nature Cancer, 2(9), 978-993. https://doi.org/10.1038/s43018-021-00237-1

Qiao, Y, Choi, JE, Tien, JC, Simko, SA, Rajendiran, T, Vo, JN, Delekta, AD, Wang, L, Xiao, L, Hodge, NB, Desai, P, Mendoza, S, Juckette, K, Xu, A, Soni, T, Su, F, Wang, R, Cao, X, Yu, J, Kryczek, I, Wang, XM, Wang, X, Siddiqui, J, Wang, Z, Bernard, A, Fernandez-Salas, E, Navone, NM, Ellison, SJ, Ding, K, Eskelinen, EL, Heath, EI, Klionsky, DJ, Zou, W & Chinnaiyan, AM 2021, 'Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer', Nature Cancer, vol. 2, no. 9, pp. 978-993. https://doi.org/10.1038/s43018-021-00237-1

@article{9b66761afce8461d8618fd9a176d2dae,

title = "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 antitumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated CXCL10 expression through the interferon-γ 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{\textquoteright}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.",

author = "Yuanyuan Qiao and Choi, {Jae Eun} and Tien, {Jean C.} and Simko, {Stephanie A.} and Thekkelnaycke Rajendiran and Vo, {Josh N.} and Delekta, {Andrew D.} and Lisha Wang and Lanbo Xiao and Hodge, {Nathan B.} and Parth Desai and Sergio Mendoza and Kristin Juckette and Alice Xu and Tanu Soni and Fengyun Su and Rui Wang and Xuhong Cao and Jiali Yu and Ilona Kryczek and Wang, {Xiao Ming} and Xiaoju Wang and Javed Siddiqui and Zhen Wang and Am{\'e}lie Bernard and Ester Fernandez-Salas and Navone, {Nora M.} and Ellison, {Stephanie J.} and Ke Ding and Eskelinen, {Eeva Liisa} and Heath, {Elisabeth I.} and Klionsky, {Daniel J.} and Weiping Zou and Chinnaiyan, {Arul M.}",

note = "Funding Information: We thank M. Trierweiler and S. Zelenka-Wang for histological sample processing and IHC, as well as undergraduate student K. Johnson for technical assistance. This work was supported by a Prostate Cancer Foundation Challenge Award, NCI Prostate SPORE Grant P50CA186786, Department of Defense PC130151P1 (to N.M.N. and A.M.C.) and NIH grant GM131919 (to D.J.K.). A.M.C. is an NCI Outstanding Investigator (R35CA231996), Howard Hughes Medical Institute Investigator, A. Alfred Taubman Scholar and American Cancer Society Professor. Y.Q. and J.C.T. are supported by Prostate Cancer Foundation Young Investigator awards. L.X. is supported by a Department of Defense Postdoctoral Award (W81XWH-16-1-0195). E.-L.E. was supported by the Academy of Finland. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = sep,

doi = "10.1038/s43018-021-00237-1",

language = "English (US)",

volume = "2",

pages = "978--993",

journal = "Nature Cancer",

issn = "2662-1347",

publisher = "Nature Research",

number = "9",

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TY - JOUR

T1 - Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer

AU - Qiao, Yuanyuan

AU - Choi, Jae Eun

AU - Tien, Jean C.

AU - Simko, Stephanie A.

AU - Rajendiran, Thekkelnaycke

AU - Vo, Josh N.

AU - Delekta, Andrew D.

AU - Wang, Lisha

AU - Xiao, Lanbo

AU - Hodge, Nathan B.

AU - Desai, Parth

AU - Mendoza, Sergio

AU - Juckette, Kristin

AU - Xu, Alice

AU - Soni, Tanu

AU - Su, Fengyun

AU - Wang, Rui

AU - Cao, Xuhong

AU - Yu, Jiali

AU - Kryczek, Ilona

AU - Wang, Xiao Ming

AU - Wang, Xiaoju

AU - Siddiqui, Javed

AU - Wang, Zhen

AU - Bernard, Amélie

AU - Fernandez-Salas, Ester

AU - Navone, Nora M.

AU - Ellison, Stephanie J.

AU - Ding, Ke

AU - Eskelinen, Eeva Liisa

AU - Heath, Elisabeth I.

AU - Klionsky, Daniel J.

AU - Zou, Weiping

AU - Chinnaiyan, Arul M.

N1 - Funding Information: We thank M. Trierweiler and S. Zelenka-Wang for histological sample processing and IHC, as well as undergraduate student K. Johnson for technical assistance. This work was supported by a Prostate Cancer Foundation Challenge Award, NCI Prostate SPORE Grant P50CA186786, Department of Defense PC130151P1 (to N.M.N. and A.M.C.) and NIH grant GM131919 (to D.J.K.). A.M.C. is an NCI Outstanding Investigator (R35CA231996), Howard Hughes Medical Institute Investigator, A. Alfred Taubman Scholar and American Cancer Society Professor. Y.Q. and J.C.T. are supported by Prostate Cancer Foundation Young Investigator awards. L.X. is supported by a Department of Defense Postdoctoral Award (W81XWH-16-1-0195). E.-L.E. was supported by the Academy of Finland. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2021/9

Y1 - 2021/9

N2 - 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-γ 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.

AB - 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-γ 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.

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JO - Nature Cancer

JF - Nature Cancer

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ER -

Autophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer

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