Selective and Potent CDK8/19 Inhibitors Enhance NK-Cell Activity and Promote Tumor Surveillance
| العنوان: | Selective and Potent CDK8/19 Inhibitors Enhance NK-Cell Activity and Promote Tumor Surveillance |
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| المؤلفون: | Segundo Gonzalez, Dirk Scharn, Mark Pearson, Sebastian Carotta, Swagata Goswami, Natarajan Muthusamy, Heribert Arnhof, Sumithira Vasu, Norbert Kraut, Seila Lorenzo-Herrero, Harald Engelhardt, Michael P. Sanderson, Marc Kerenyi, Maria Antonietta Impagnatiello, Rajeswaran Mani, Renate Schnitzer, Jark Böttcher, Peter Ettmayer, Girish Rajgolikar, Marco H. Hofmann, Jürgen Moll, Andreas Zoephel, Darryl B. McConnell, Thomas Gerstberger |
| المصدر: | Mol Cancer Ther |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Cytotoxicity, Immunologic, 0301 basic medicine, Cancer Research, Melanoma, Experimental, Apoptosis, Breast Neoplasms, Mice, SCID, Article, GZMB, Mice, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, Tumor Cells, Cultured, medicine, Animals, Humans, Phosphorylation, Protein Kinase Inhibitors, Cell Proliferation, biology, Chemistry, Degranulation, Cancer, Cyclin-Dependent Kinase 8, Acquired immune system, medicine.disease, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinases, Killer Cells, Natural, Mice, Inbred C57BL, Granzyme B, Leukemia, Myeloid, Acute, STAT1 Transcription Factor, 030104 developmental biology, Oncology, Perforin, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, biology.protein, Female, Antibody |
| الوصف: | Natural killer (NK) cells play a pivotal role in controlling cancer. Multiple extracellular receptors and internal signaling nodes tightly regulate NK activation. Cyclin-dependent kinases of the mediator complex (CDK8 and CDK19) were described as a signaling intermediates in NK cells. Here, we report for the first time the development and use of CDK8/19 inhibitors to suppress phosphorylation of STAT1S727 in NK cells and to augment the production of the cytolytic molecules perforin and granzyme B (GZMB). Functionally, this resulted in enhanced NK-cell–mediated lysis of primary leukemia cells. Treatment with the CDK8/19 inhibitor BI-1347 increased the response rate and survival of mice bearing melanoma and breast cancer xenografts. In addition, CDK8/19 inhibition augmented the antitumoral activity of anti–PD-1 antibody and SMAC mimetic therapy, both agents that promote T-cell–mediated antitumor immunity. Treatment with the SMAC mimetic compound BI-8382 resulted in an increased number of NK cells infiltrating EMT6 tumors. Combination of the CDK8/19 inhibitor BI-1347, which augments the amount of degranulation enzymes, with the SMAC mimetic BI-8382 resulted in increased survival of mice carrying the EMT6 breast cancer model. The observed survival benefit was dependent on an intermittent treatment schedule of BI-1347, suggesting the importance of circumventing a hyporesponsive state of NK cells. These results suggest that CDK8/19 inhibitors can be combined with modulators of the adaptive immune system to inhibit the growth of solid tumors, independent of their activity on cancer cells, but rather through promoting NK-cell function. |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7eaac64dc345ae1363e27768a9e757d9 https://doi.org/10.1158/1535-7163.mct-19-0789 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....7eaac64dc345ae1363e27768a9e757d9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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