Abstract 6175: CDK8 inhibition potentiates the efficacy of niraparib in homologous recombination proficient cancer cell lines
Authors: Simon-Crevatis Karen A. , Metkar Shailesh R. , Hardcastle Justin T. , Jansson Keith , Shabon Usman , Choudhury Rajarshi , Stronach Euan A. , Coleman Kevin G. , Muvaffak Asli 
Published: April 2023

Abstract
While cyclin dependent kinases (CDKs) were originally implicated in cell cycle regulation, several CDKs including CDK7, CDK8, and CDK9 play critical roles in transcription through regulation of RNA polymerase II (Pol II) activity. In addition to expected phosphosite targets associated with DNA-binding transcription factors, chromatin regulators, or other known regulators of pol II activity, a phospho-proteomics study on a CDK8/19 inhibitor (Cortistatin A) also identified DNA replication and repair proteins, i.e., namely BRCA1 and MDC1, as substrates for CDK8. RVU120, a first in-class CDK8/19 inhibitor in phase I clinical trial demonstrated preclinical efficacy in acute myeloid leukemia PDX models. A robust relationship has also been observed between the exposure to RVU120 and inhibition of pSTAT5, a pharmacodynamic marker, in solid tumor indications in a recent clinical trial. Additionally, preclinical data suggested RVU120 reduced expression of genes related to interferon-related DNA damage signature (IRDS) suggesting a potential role of CDK8 in DNA repair signaling.
CDK8 loss was identified as a synthetic lethal hit in two internal, orthogonal screens that surveyed targets which can synergize with niraparib inhibition. Niraparib inhibits PARP enzymatic activity and promotes PARP trapping on ssDNA breaks which lead to replication stress-induced dsDNA breaks that require BRCA-dependent homologous recombination repair (HRR). Combination with other therapeutic agents is anticipated to improve the efficacy of niraparib in HR proficient (HRP) and BRCA1/2.WT tumors. This work describes our proof-of-concept data from in vitro validation of combination synergy response of RVU120 with niraparib in a panel of 129 HRR.WT and HRR mutant cancer cell lines across ovarian, breast, lung, and colorectal cancer indications. Our results indicated that the niraparib+RVU120 combination was synergistic, and a strong synergy response, i.e., a SS (Synergy Score) ≥ 5 was detected by Loewe modelling across the entire surface of the combination matrix in ~26% of Horizon Discovery OncoSignatureTM panel cell lines that were largely resistant to niraparib monotherapy. The study findings indicated the potential of CDK8/19 inhibitors to enhance niraparib activity in both HRR.WT and HRR mutant populations. The potential benefit of CDK8/19i+niraparib combination will be further explored in PARPi-resistant models. Molecular studies are underway to explore potential biomarkers associated with synergy response, and to analyze the downstream effects on DNA Damage Response.
Citation Format: Karen A. Simon-Crevatis, Shailesh R. Metkar, Justin T. Hardcastle, Keith Jansson, Usman Shabon, Rajarshi Choudhury, Euan A. Stronach, Kevin G. Coleman, Asli Muvaffak. CDK8 inhibition potentiates the efficacy of niraparib in homologous recombination proficient cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6175.