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

Abstract

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.

The Mediator kinase module: an interface between cell signaling and transcription

“…If the link between expression of AP-1 subunits and Mediator kinase module function is shared across cell types, it could help explain many phenotypes associated with Mediator kinase module inhibition or mutation. For example, proliferation [26,31,51], drug resistance [33,82], and cell migration [83,84] are each linked to the Mediator kinase module and each is impacted by AP-1 TFs [85,86].…”

Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo

“…We have also tested the effects of CDK8/19i on the development of adaptive lapatinib resistance in a previously described short-term single-step adaptation procedure ( 29 ). Both SKBR3 ( Fig.…”

Identification of Cdk8 and Cdkn2d as New Prame-Target Genes in 2C-like Embryonic Stem Cells

“…Being involved in the regulation of cell cycle checkpoints, Cdk8, and Cdkn2d are involved in several cellular pathways, however, very little is known about their involvement in the establishment of RA-resistant Zscan4 metastate pluripotent cells. CDK8 was shown to maintain tumor dedifferentiation and embryonic stem cells pluripotency stage [ 16 ] drugs resistance in several cancer disease models [ 36 , 37 ]. Similar evidence was reported for Cdkn2d overexpression [ 38 ].…”