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Full-Text Articles in Medicine and Health Sciences
The Inhibition Of Cdk8/19 Mediator Kinases Prevents The Development Of Resistance To Egfr-Targeting Drugs, Amanda C. Sharko, Chang-Uk Lim, Martina S.J. Mcdermott, Chuck Hennes, Kingsavanh P. Philavong, Tiffanie Aiken, Victor V. Tatarskiy, Igor Roninson Ph. D., Eugenia Broude
The Inhibition Of Cdk8/19 Mediator Kinases Prevents The Development Of Resistance To Egfr-Targeting Drugs, Amanda C. Sharko, Chang-Uk Lim, Martina S.J. Mcdermott, Chuck Hennes, Kingsavanh P. Philavong, Tiffanie Aiken, Victor V. Tatarskiy, Igor Roninson Ph. D., Eugenia Broude
Faculty Publications
Drug resistance is the main obstacle to achieving cures with both conventional and targeted anticancer drugs. The emergence of acquired drug resistance is initially mediated by non-genetic transcriptional changes, which occur at a much higher frequency than mutations and may involve population-scale transcriptomic adaptation. CDK8/19 kinases, through association with transcriptional Mediator complex, regulate transcriptional reprogramming by co-operating with different signal-responsive transcription factors. Here we tested if CDK8/19 inhibition could prevent adaptation to drugs acting on epidermal growth factor receptor (EGFR/ERBB1/HER1). The development of resistance was analyzed following long-term exposure of BT474 and SKBR3 breast cancer cells to EGFR-targeting small molecules …
Systemic Toxicity Reported For Cdk8/19 Inhibitors Cct251921 And Msc2530818 Is Not Due To Target Inhibition, Mengqian Chen, Jing Li, Jiaxin Liang, Zanshé S. Thompson, Katie Kathrein, Eugenia Broude, Igor Roninson
Systemic Toxicity Reported For Cdk8/19 Inhibitors Cct251921 And Msc2530818 Is Not Due To Target Inhibition, Mengqian Chen, Jing Li, Jiaxin Liang, Zanshé S. Thompson, Katie Kathrein, Eugenia Broude, Igor Roninson
Faculty Publications
CDK8/19 kinases, which mediate transcriptional reprogramming, have become an active target for cancer drug discovery. Several small-molecule CDK8/19 inhibitors showed in vivo efficacy and two have entered clinical trials, with no significant toxicities reported. However, Clarke et al. (eLife 2016; 5; e20722) found severe systemic toxicity associated with two potent CDK8/19 inhibitors, Cmpd3 (CCT251921) and Cmpd4 (MSC2530818), and suggested that their toxicity was due to on-target effects. Here, we compared five CDK8/19 inhibitors: Cmpd3, Cmpd4, Senexin B, 16-didehydro-cortistatin A (dCA) and 15w, in different assays. Only Cmpd4 showed striking toxicity in developing zebrafish. In cell-based assays for CDK8 and CDK19 …
Identifying Cancers For Cdk8/19 Inhibitor Therapy, Igor Roninson, Balázs Győrffy, Zachary T. Mack, Alexander A. Shtil, Michael S. Shtutman, Mengqian Chen, Eugenia Broude
Identifying Cancers For Cdk8/19 Inhibitor Therapy, Igor Roninson, Balázs Győrffy, Zachary T. Mack, Alexander A. Shtil, Michael S. Shtutman, Mengqian Chen, Eugenia Broude
Faculty Publications
CDK8 and CDK19 Mediator kinases are transcriptional co-regulators implicated in several types of cancer. Small-molecule CDK8/19 inhibitors have recently entered or are entering clinical trials, starting with breast cancer and acute myeloid leukemia (AML). To identify other cancers where these novel drugs may provide benefit, we queried genomic and transcriptomic databases for potential impact of CDK8, CDK19, or their binding partner CCNC. sgRNA analysis of a panel of tumor cell lines showed that most tumor types represented in the panel, except for some central nervous system tumors, were not dependent on these genes. In contrast, analysis of clinical samples for …