Selective and Potent CDK8/19 Inhibitors Enhance NK-Cell Activity and Promote Tumor Surveillance

Abstract

◥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 STAT1 S727 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 anti-body and SMAC mimetic therapy, both agents that promote T-cellmediated 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.

Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks

“…inhibitors; (Hofmann et al, 2020;Solum et al, 2020)) could be leveraged as a therapy to disrupt SARS-CoV-2 infection (Bancerek et al, 2013;Napoli et al, 2012;Spaeth et al, 2011).…”

Natural Killer Cells in Immunotherapy: Are We Nearly There?

“…Interestingly, a novel molecule comprising N-803 and anti-PD-L1 domains has shown promise for different carcinoma models [144]. Another study showed that a CDK8/CDK19 inhibitor, which augments NK cell activity, improved anti-PD-1 treatment in the tumor model with MC38 colon adenocarcinoma cells [146]. Beyond PD-1, a combination of anti-TIGIT or anti-KLRG1 antibodies and DNA methyltransferase inhibitor reversed the metastasis-promoting state acquired by certain tumor-exposed NK cells [147].…”

CDK19 as a Potential HPV-Independent Biomarker for Recurrent Disease in HNSCC

“…CDK19 and its paralog CDK8 are known to promote different cancer-related pathways in several solid tumors, such as TGF-β/BMP-induced epithelial–mesenchymal-transition (EMT), and NFκB-mediated gene transcription [ 7 , 8 , 10 , 11 ]. Recently, CDK19 and CDK8 emerged as promising potential therapeutic targets in cancer therapy [ 24 , 25 , 26 , 27 ].…”

“…Based on these observations, CDK19 emerged as a promising therapeutic target in different tumor types, leading to the development of small-molecule inhibitors impeding the activity of CDK19 and its paralog CDK8 [ 24 , 25 , 26 , 27 ].…”