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Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer.
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.
Afiliação
  • Qiao Y; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Choi JE; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Tien JC; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • Simko SA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Rajendiran T; School of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Vo JN; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Delekta AD; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Wang L; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Xiao L; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Hodge NB; Michigan Regional Comprehensive Metabolomics Resource Core, Ann Arbor, MI, USA.
  • Desai P; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Mendoza S; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Juckette K; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Xu A; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Soni T; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Su F; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Wang R; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Cao X; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Yu J; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Kryczek I; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Wang XM; Michigan Regional Comprehensive Metabolomics Resource Core, Ann Arbor, MI, USA.
  • Wang X; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Siddiqui J; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Wang Z; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Bernard A; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
  • Fernandez-Salas E; Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Navone NM; Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Ellison SJ; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Ding K; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Eskelinen EL; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Heath EI; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Klionsky DJ; School of Pharmacy, Jinan University, Guangzhou, China.
  • Zou W; CNRS, Laboratoire de Biogenèse Membranaire, Université de Bordeaux, Bordeaux, France.
  • Chinnaiyan AM; Life Sciences Institute, Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
Nat Cancer ; 2: 978-993, 2021 09.
Article em En | MEDLINE | ID: mdl-34738088
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias de Próstata Resistentes à Castração / Inibidores de Checkpoint Imunológico Limite: Humans / Male Idioma: En Revista: Nat Cancer Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias de Próstata Resistentes à Castração / Inibidores de Checkpoint Imunológico Limite: Humans / Male Idioma: En Revista: Nat Cancer Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos