8rxr
Crystal structure of VPS34 in complex with inhibitor SB02024
Structural highlights
FunctionPK3C3_HUMAN Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes.[1] [2] [3] Publication Abstract from PubMedAn immunosuppressive tumor microenvironment promotes tumor growth and is one of the main factors limiting the response to cancer immunotherapy. We have previously reported that inhibition of vacuolar protein sorting 34 (VPS34), a crucial lipid kinase in the autophagy/endosomal trafficking pathway, decreases tumor growth in several cancer models, increases infiltration of immune cells and sensitizes tumors to anti-programmed cell death protein 1/programmed cell death 1 ligand 1 therapy by upregulation of C-C motif chemokine 5 (CCL5) and C-X-C motif chemokine 10 (CXCL10) chemokines. The purpose of this study was to investigate the signaling mechanism leading to the VPS34-dependent chemokine increase. NanoString gene expression analysis was applied to tumors from mice treated with the VPS34 inhibitor SB02024 to identify key pathways involved in the anti-tumor response. We showed that VPS34 inhibitors increased the secretion of T-cell-recruitment chemokines in a cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING)-dependent manner in cancer cells. Both pharmacological and small interfering RNA (siRNA)-mediated VPS34 inhibition increased cGAS/STING-mediated expression and secretion of CCL5 and CXCL10. The combination of VPS34 inhibitor and STING agonist further induced cytokine release in both human and murine cancer cells as well as monocytic or dendritic innate immune cells. Finally, the VPS34 inhibitor SB02024 sensitized B16-F10 tumor-bearing mice to STING agonist treatment and significantly improved mice survival. These results show that VPS34 inhibition augments the cGAS/STING pathway, leading to greater tumor control through immune-mediated mechanisms. We propose that pharmacological VPS34 inhibition may synergize with emerging therapies targeting the cGAS/STING pathway. Combining VPS34 inhibitors with STING agonists enhances type I interferon signaling and anti-tumor efficacy.,Yu Y, Bogdan M, Noman MZ, Parpal S, Bartolini E, Van Moer K, Kleinendorst SC, Bilgrav Saether K, Tresaugues L, Silvander C, Lindstrom J, Simeon J, Timson MJ, Al-Hashimi H, Smith BD, Flynn DL, Alexeyenko A, Viklund J, Andersson M, Martinsson J, Pokrovskaja Tamm K, De Milito A, Janji B Mol Oncol. 2024 Aug;18(8):1904-1922. doi: 10.1002/1878-0261.13619. Epub 2024 Mar , 20. PMID:38506049[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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