Targeting DGKα/PA axis inhibits tumor immune evasion and augments sensitivity to immunotherapy in gastrointestinal cancers

References

[1] Mizrahi, Jonathan, and Shubham Pant. 2020. “Immunotherapy in Gastrointestinal Malignancies.” Advances in Experimental Medicine and Biology 1244: 93–106. https://doi.org/10.1007/978-3-030-41008-7_5

[2] Li, Jiannan, Wei Li, Lanqing Cao, Ning Liu, and Kai Zhang. 2020. “Efficacy of Mesenchymal Stem Cells in the Treatment of Gastrointestinal Malignancies.” World Journal of Gastrointestinal Oncology 12: 365–82. https://doi.org/10.4251/wjgo.v12.i4.365

[3] Yang, Zhenjie, Jun Yu, and Chi Chun Wong. 2024. “Gastrointestinal Cancer Patient Derived Organoids at the Frontier of Personalized Medicine and Drug Screening.” Cells 13: 1312. https://doi.org/10.3390/cells13161312

[4] Catenacci, Daniel V., Joseph Chao, Kei Muro, Salah Eddin Al-Batran, Samuel J. Klempner, Zev A. Wainberg, Manish A. Shah, et al. 2021. “Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma.” The Oncologist 26: e1704–29. https://doi.org/10.1002/onco.13907

[5] Lim, Hyung-Kyu, Kyu , Young Ae Choi, Wan Park, Taehoon Lee, Sung Ho Ryu, Seong Yong Kim, Jae Ryong Kim, Jung-Hye Kim, and Suk-Hwan Baek. 2003. “Phosphatidic Acid Regulates Systemic Inflammatory Responses by Modulating the Akt-Mammalian Target of rapamycin-p70 S6 Kinase 1 Pathway.” Journal of Biological Chemistry 278: 45117–27. https://doi.org/10.1074/jbc.M303789200

[6] Shulga, Yulia V., Matthew K. Topham, and Richard M. Epand. 2011. “Regulation and Functions of Diacylglycerol Kinases.” Chemical Reviews 111: 6186–208. https://doi.org/10.1021/cr1004106

[7] Topham, Matthew K. 2006. “Signaling Roles of Diacylglycerol Kinases.” Journal of Cellular Biochemistry 97: 474–84. https://doi.org/10.1002/jcb.20704

[8] Liu, Weiren, Huqiang Wang, Qianfu Zhao, Chenyang Tao, Weifeng Qu, Yushan Hou, Run Huang, et al. 2024. “Multiomics Analysis Reveals Metabolic Subtypes and Identifies Diacylglycerol Kinase α (DGKA) as a Potential Therapeutic Target for Intrahepatic Cholangiocarcinoma.” Cancer Communications 44: 226–50. https://doi.org/10.1002/cac2.12513

[9] Dominguez, Charli L., Desiree H. Floyd, Aizhen Xiao, Garrett R. Mullins, Benjamin A. Kefas, Wenjun Xin, Melissa N. Yacur, et al. 2013. “Diacylglycerol Kinase α Is a Critical Signaling Node and Novel Therapeutic Target in Glioblastoma and Other Cancers.” Cancer Discovery 3: 782–97. https://doi.org/10.1158/2159-8290.CD-12-0215

[10] Chen, Jie, Di Zhao, Lingyuan Zhang, Jing Zhang, Yuanfan Xiao, Qingnan Wu, Yan Wang, and Qimin Zhan. 2024. “Tumor-Associated Macrophage (TAM)-secreted CCL22 Confers Cisplatin Resistance of Esophageal Squamous Cell Carcinoma (ESCC) Cells Via Regulating the Activity of Diacylglycerol Kinase α (DGKα)/NOX4 Axis.” Drug Resistance Updates 73: 101055. https://doi.org/10.1016/j.drup.2024.101055

[11] Velnati, Suresh, Elisa Ruffo, Alberto Massarotti, Maria Talmon, Konduru Sai Sandeep Varma, Alessandro Gesu, Luigia Grazia Fresu, et al. 2019. “Identification of a Novel DGKα Inhibitor for XLP-1 Therapy by Virtual Screening.” European Journal of Medicinal Chemistry 164: 378–90. https://doi.org/10.1016/j.ejmech.2018.12.061

[12] Boroda, Salome, Maria Niccum, Vidisha Raje, Benjamin W. Purow, and Thurl E. Harris. 2017. “Dual Activities of Ritanserin and R59022 as DGKα Inhibitors and Serotonin Receptor Antagonists.” Biochemical Pharmacology 123: 29–39. https://doi.org/10.1016/j.bcp.2016.10.011

[13] Sawatani, Toshiaki, Yukiko K. Kaneko, and Tomohisa Ishikawa. 2019. “Dual Effect of Reduced Type I Diacylglycerol Kinase Activity on Insulin Secretion From MIN6 β-cells.” Journal of Pharmacological Sciences 140: 178–86. https://doi.org/10.1016/j.jphs.2019.06.001

[14] Soula, Mariluz, Gokhan Unlu, Rachel Welch, Aleksey Chudnovskiy, Beste Uygur, Vyom Shah, Hanan Alwaseem, et al. 2024. “Glycosphingolipid Synthesis Mediates Immune Evasion in KRAS-Driven Cancer.” Nature 633: 451–8. https://doi.org/10.1038/s41586-024-07787-1

[15] Luu, Maik, Zeno Riester, Adrian Baldrich, Nicole Reichardt, Samantha Yuille, Alessandro Busetti, Matthias Klein, et al. 2021. “Microbial Short-Chain Fatty Acids Modulate CD8+ T Cell Responses and Improve Adoptive Immunotherapy for Cancer.” Nature Communications 12: 4077. https://doi.org/10.1038/s41467-021-24331-1

[16] Yan, Yuheng, Lan Huang, Yiming Liu, Ming Yi, Qian Chu, Dechao Jiao, and Kongming Wu. 2022. “Metabolic Profiles of Regulatory T Cells and Their Adaptations to the Tumor Microenvironment: Implications for Antitumor Immunity.” Journal of Hematology & Oncology 15: 104. https://doi.org/10.1186/s13045-022-01322-3

[17] Kai, Masahiro, Satoshi Yasuda, Shin-ichi Imai, Minoru Toyota, Hideo Kanoh, and Fumio Sakane. 2009. “Diacylglycerol Kinase α Enhances Protein Kinase Cζ-Dependent Phosphorylation at Ser311 of p65/RelA Subunit of Nuclear Factor-κB.” FEBS Letters 583: 3265–8. https://doi.org/10.1016/j.febslet.2009.09.017

[18] Kang, Hyunkoo, Haksoo Lee, Kyeongmin Kim, Eunguk Shin, Byeongsoo Kim, JiHoon Kang, Bohkyung Kim, et al. 2023. “DGKB Mediates Radioresistance by Regulating DGAT1-Dependent Lipotoxicity in Glioblastoma.” Cell Reports Medicine 4: 100880. https://doi.org/10.1016/j.xcrm.2022.100880

[19] Zhang, Hao, Ziyu Dai, Wantao Wu, Zeyu Wang, Nan Zhang, Liyang Zhang, WenJing Zeng, et al. 2021. “Regulatory Mechanisms of Immune Checkpoints PD-L1 and CTLA-4 in Cancer.” Journal of Experimental & Clinical Cancer Research 40: 184. https://doi.org/10.1186/s13046-021-01987-7

[20] O'Malley, David M., Maryna Neffa, Bradley J. Monk, Tamar Melkadze, Marilyn Huang, Anna Kryzhanivska, Iurie Bulat, et al. 2022. “Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study.” Journal of Clinical Oncology 40: 762–71. https://doi.org/10.1200/JCO.21.02067

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