Abstract 510: Selective and potent CDK8 inhibitors enhance NK cell activity and promote tumor surveillance

Abstract

Abstract Natural killer (NK) cells play a pivotal role in controlling cancer. Activation of NK cells is tightly regulated by multiple extracellular receptors and internal signaling nodes. The production of perforin and granzyme B, key NK cytolytic molecules, is regulated by the suppressive signaling intermediate Cyclin Dependent Kinase 8 (CDK8) through phosphorylation and inhibition of STAT1S727. We identified highly potent and selective CDK8 inhibitors, including BI-9811 and BI-1347, that we previously reported as valuable probe compounds (Hofmann M.H. et al., AACR Annual Meeting 2017, Abstract 4630). CDK8 inhibition promoted activation of NK cells but had no direct cytotoxic activity on the majority of cancer cell lines tested. Single agent treatment with the CDK8 inhibitor BI-1347 increased the survival of mice bearing melanoma and breast cancer allografts. In addition to this, treatment with BI-1347 resulted in enhanced NK-cell mediated lysis of myeloid leukaemia and lymphoma cells. We evaluated whether increased efficacy could be observed upon activation of both the innate and the adaptive immune system by combining the CDK8 inhibitor with a SMAC mimetic. SMAC mimetic treatment enhanced T-cell activity and increased NK cell number in the murine EMT6 breast cancer model. Increased survival upon combination treatment was dependent on a pulsatile schedule of the CDK8 inhibitor BI-1347, which permitted activation of NK cells but avoided a hypo-responsive steady state. These results demonstrate that CDK8 inhibitors could be used either as a single agent in hematological cancers or be combined with modulators of the adaptive immune system to inhibit the growth of solid tumors. Citation Format: Marco H. Hofmann, Rajeswaran Mani, Harald Engelhardt, Maria A. Impagnatiello, Sebastian Carotta, Marc A. Kerenyi, Seila Lorenzo-Herrero, Jark Boettcher, Dirk Scharn, Heribert Arnhof, Andreas Zoephel, Renate Schnitzer, Thomas Gerstberger, Girish Rajgolikar, Swagata Goswami, Sumithira Vasu, Peter Ettmayer, Segundo R. Gonzalez, Mark Pearson, Darryl B. McConnell, Norbert Kraut, Natarajan Muthusamy, Juergen Moll. Selective and potent CDK8 inhibitors enhance NK cell activity and promote tumor surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 510.