Abstract 5712: Functional dissection of CDK7 in transcription using a highly selective CDK7 inhibitor Q901

Abstract

Abstract CDK7 is a well-known regulator of both the cell cycle and transcription and plays a crucial role in cell cycle progression by catalyzing T-loop phosphorylation of other CDKs. CDK7 is also an integral subunit of the general transcription factor, TFIIH and regulates transcription through phosphorylation of RNA Polymerase II (Pol II) at CTD Ser5 and CDK9. We used Q901, a highly selective CDK7 inhibitor to further investigate the molecular function of CDK7 in the transcriptional process. Q901 is currently being evaluated in a phase 1 clinical study for selected advanced solid tumors. Compared to previously reported CDK7 inhibitors, Q901 has increased specificity and efficacy, but the impact on transcription have not been studied in detail. In our study, we combined RNA Pol II (pan, Ser5P, Ser2P) ChIP-seq and PRO-seq techniques in the MCF7 breast cancer cell line. The findings demonstrated that the Q901 effectively altered transcription and the RNA Pol II profile in a subset of genes, leading to a significant reduction in Ser5 phosphorylation levels in RNA Pol II. The downregulated genes were associated with critical pathways including downstream of oncogenic genes (MYC and E2F), DNA damage repair, cell cycle checkpoint, and gene expression. To verify whether these genes were the direct targets of CDK7, we performed CDK7 ChIP-seq analysis. CDK7 binding exclusively to the genes that were downregulated by Q901, without any detectable binding to upregulated genes. Despite the universal role of general transcription machinery in transcription, the data demonstrated that the highly selective inhibition of CDK7 in transcription of various oncogenic pathways underlies the potent in vitro and in vivo anti-cancer efficacy of this specific CDK7 inhibitor. Citation Format: Hyerim Jung, Dahun Um, Yoonji Lee, Donghoon Yu, Dayoung Lee, Jiye Ahn, Jeongjun Kim, Seung-Joo Lee, Jaeseung Kim, Kiyean Nam, Tae-Kyung Kim. Functional dissection of CDK7 in transcription using a highly selective CDK7 inhibitor Q901 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5712.