Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer.
Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer.
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靶向PIKfyve的自噬抑制增强了前列腺癌对免疫检查点阻断的反应。
DOI：
10.1038/s43018-021-00237-1
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发表时间：
2021-09
期刊：
影响因子：
22.7
通讯作者：
Chinnaiyan AM
中科院分区：
文献类型：
--
作者：
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
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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影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
7.3
作者：
Hudkins, Robert L.;Becknell, Nadine C.;Ruggeri, Bruce A.
通讯作者：
Ruggeri, Bruce A.
影响因子：
6
作者：
Afshinnia F;Rajendiran TM;Karnovsky A;Soni T;Wang X;Xie D;Yang W;Shafi T;Weir MR;He J;Brecklin CS;Rhee EP;Schelling JR;Ojo A;Feldman H;Michailidis G;Pennathur S
通讯作者：
Pennathur S
DOI：
10.1007/978-1-4939-6996-8_14
发表时间：
2017-01-01
期刊：
LIPIDOMICS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Cajka, Tomas;Fiehn, Oliver
通讯作者：
Fiehn, Oliver