Abstract P4-01-17: Preventing adaptive therapeutic resistance to CDK4/6 inhibition with CDK8/19 inhibitors
Authors: Mack Zachary , Yastrebova Margarita , Khamidullina Alvina , Sharko Amanda , Ding Xiaokai , Bowe Stephan , Sashi Nikitha , Safa Samantha , Digsby Kaitlyn , Eckstrom Amanda , Sikirzhitski Vitali , Lim Chang-uk , Tatarskiy Victor , Roninson Igor , Broude Eugenia 
Published: March 2022

Abstract
Inhibitors of CDK4/6 have provided a major addition to the clinical armamentarium in estrogen receptor (ER)-positive breast cancers. Palbociclib and other FDA-approved CDK4/6 inhibitors slow down tumor growth and induce senescence (irreversible cell cycle arrest) by inhibiting downstream phosphorylation of the Rb protein by the CDK4/6-Cyclin D complex. However, long-term treatment with CDK4/6 inhibitors inevitably leads to drug resistance and an overall decline in drug efficacy, both in laboratory models and in the clinic. Therefore, identifying an approach to preventing the development of resistance to CDK4/6 inhibitors would be beneficial to improving patient outcomes.CDK8 or its isoform, CDK19, together with their binding partner Cyclin C (CCNC) and proteins MED12 and MED13, form the regulatory CDK module of the transcriptional Mediator complex. CDK8/19 are actively pursued drug targets, with highly selective pharmacological inhibitors of CDK8/19 becoming available. The primary function of CDK8/19 Mediator kinase is potentiation of several signal-responsive transcription factors, such as ER, NFκB, SMADs, STATs and HIF1α; CDK8/19 inhibition suppresses signal-induced expression of a subset of genes activated by such transcription factors. This function defines CDK8/19 as mediators of transcriptional reprogramming, a critical process for the development of drug resistance, and CDK8/19 inhibition has been found to prevent the development of resistance to several classes of anticancer drugs. We have now tested if selective CDK8/19 inhibitors, Senexin B and SNX631, could prevent the development of Palbociclib resistance in ER-positive breast cancers. Our experiments have shown that Palbociclib-treated ER-positive breast cell lines, when cultured in the presence of Palbociclib, rapidly become resistant. CDK8/19 inhibitors have only a moderate growth-inhibitory effect in these cells and do not overcome acquired Palbociclib resistance. However, when CDK8/19 inhibitors are added together with Palbociclib, resistance does not develop. We have found that CDK8/19 inhibitors counteract some of the transcriptomic effects of Palbociclib and interact with this drug in modulating Rb expression and phosphorylation and attenuating the senescent phenotype. These results suggest specific mechanisms through which CDK8/19 inhibition prevents the development of adaptive resistance to Palbociclib. These in vitro findings are currently being investigated in vivo in an ER-positive breast cancer xenograft model.
Citation Format: Zachary Mack, Margarita Yastrebova, Alvina Khamidullina, Amanda Sharko, Xiaokai Ding, Stephan Bowe, Nikitha Sashi, Samantha Safa, Kaitlyn Digsby, Amanda Eckstrom, Vitali Sikirzhitski, Chang-uk Lim, Victor Tatarskiy, Igor Roninson, Eugenia Broude. Preventing adaptive therapeutic resistance to CDK4/6 inhibition with CDK8/19 inhibitors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-17.