The Inhibition of CDK8/19 Mediator Kinases Prevents the Development of Resistance to EGFR-Targeting Drugs

Cells

Chuck Hennes¹  AmandaC. Sharko¹  IgorB. Roninson¹  KingsavanhP. Philavong¹  Martina S. J. McDermott¹  Chang-Uk Lim¹  Tiffanie Aiken¹  EugeniaV. Broude¹  VictorV. Tatarskiy² 

[1] Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA;Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia;

关键词: CDK8;    CDK19;    EGFR;    gefitinib;    erlotinib;    cetuximab;   

DOI  :  10.3390/cells10010144

来源: DOAJ

【 摘 要 】

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 (gefitinib, erlotinib) and of SW48 colon cancer cells to an anti-EGFR monoclonal antibody cetuximab. In all cases, treatment of small cell populations (~10⁵ cells) with a single dose of the drug initially led to growth inhibition that was followed by the resumption of proliferation and development of drug resistance in the adapted populations. However, this adaptation was always prevented by the addition of selective CDK8/19 inhibitors, even though such inhibitors alone had only moderate or no effect on cell growth. These results indicate that combining EGFR-targeting drugs with CDK8/19 inhibitors may delay or prevent the development of tumor resistance to therapy.

【 授权许可】

Unknown