論文 - 詳細
| RRC ID | 76360 |
|---|---|
| 著者 | 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. |
| タイトル | Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer. |
| ジャーナル | Nat 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 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. |
| 巻・号 | 2 |
| ページ | 978-993 |
| 公開日 | 2021-9-1 |
| DOI | 10.1038/s43018-021-00237-1 |
| PII | 10.1038/s43018-021-00237-1 |
| PMID | 34738088 |
| PMC | PMC8562569 |
| MeSH | Autophagy Humans Immune Checkpoint Inhibitors* Immunotherapy / methods Male Phosphatidylinositol 3-Kinases / pharmacology Prostatic Neoplasms, Castration-Resistant* / drug therapy Tumor Microenvironment |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 34 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| ヒト・動物細胞 | Atg5^(+/+)MEF(RCB2710) Atg5^(-/-)MEF(RCB2711) |