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

dc.rights.licenseopenen_US
dc.contributor.authorQIAO, Y.
dc.contributor.authorCHOI, J.E.
dc.contributor.authorTIEN, J.C.
dc.contributor.authorSIMKO, S.A.
dc.contributor.authorRAJENDIRAN, T.
dc.contributor.authorVO, J.N.
dc.contributor.authorDELEKTA, A.D.
dc.contributor.authorWANG, L.
dc.contributor.authorXIAO, L.
dc.contributor.authorHODGE, N.B.
dc.contributor.authorDESAI, P.
dc.contributor.authorMENDOZA, S.
dc.contributor.authorJUCKETTE, K.
dc.contributor.authorXU, A.
dc.contributor.authorSONI, T.
dc.contributor.authorSU, F.
dc.contributor.authorWANG, R.
dc.contributor.authorCAO, X.
dc.contributor.authorYU, J.
dc.contributor.authorKRYCZEK, I.
dc.contributor.authorWANG, X.-M.
dc.contributor.authorWANG, X.
dc.contributor.authorSIDDIQUI, J.
dc.contributor.authorWANG, Z.
hal.structure.identifierLaboratoire de biogenèse membranaire [LBM]
dc.contributor.authorBERNARD, Amélie
dc.contributor.authorFERNANDEZ-SALAS, E.
dc.contributor.authorNAVONE, N.M.
dc.contributor.authorELLISON, S.J.
dc.contributor.authorDING, K.
dc.contributor.authorESKELINEN, E.-L.
dc.contributor.authorHEATH, E.I.
dc.contributor.authorKLIONSKY, D.J.
dc.contributor.authorZOU, W.
dc.contributor.authorCHINNAIYAN, A.M.
dc.date.accessioned2022-03-09T13:54:58Z
dc.date.available2022-03-09T13:54:58Z
dc.date.issued2021
dc.identifier.issn26621347en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/136401
dc.description.abstractEnMulti-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.
dc.language.isoENen_US
dc.title.enAutophagy inhibition by targeting PIKfyve potentiates response to immune checkpoint blockade in prostate cancer
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s43018-021-00237-1en_US
dc.subject.halSciences du Vivant [q-bio]en_US
dc.identifier.pubmed34738088en_US
bordeaux.journalNature Canceren_US
bordeaux.page978-993en_US
bordeaux.volume2en_US
bordeaux.hal.laboratoriesLaboratoire de Biogenèse Membranaire (LBM) - UMR 5200en_US
bordeaux.issue9en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionCNRSen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.identifier.funderIDProstate Cancer Foundationen_US
hal.exportfalse
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Nature%20Cancer&rft.date=2021&rft.volume=2&rft.issue=9&rft.spage=978-993&rft.epage=978-993&rft.eissn=26621347&rft.issn=26621347&rft.au=QIAO,%20Y.&CHOI,%20J.E.&TIEN,%20J.C.&SIMKO,%20S.A.&RAJENDIRAN,%20T.&rft.genre=article


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