# The Emerging Role of Transcription-Associated Cyclin-Dependent Kinases in Gastrointestinal Tumors

## TL;DR

This review explores how transcription-associated cyclin-dependent kinases (tCDKs) contribute to gastrointestinal cancers and discusses potential therapies targeting them.

## Contribution

The paper provides a comprehensive overview of tCDKs' roles in gastrointestinal tumors and evaluates emerging therapeutic strategies.

## Key findings

- tCDKs are overexpressed in gastrointestinal tumor tissues and contribute to transcriptional addiction in cancer cells.
- Targeting tCDKs with inhibitors or degraders shows therapeutic potential in preclinical and clinical studies.
- tCDKs regulate super enhancer regions, which are linked to cancer cell proliferation and survival.

## Abstract

Transcription-associated cyclin-dependent kinases (tCDKs) play critical roles in regulating RNA polymerase II activity and gene transcription. Many cancers, including gastrointestinal (GI) tumors, become unusually dependent on enhanced-transcriptional activity (“transcriptional addiction”) that promotes cancer cell proliferation, survival, and aggressiveness. This review summarizes the cancer-specific functions and clinical relevance of tCDKs (including CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, and CDK19), with a particular focus on GI tumors (esophageal, gastric, pancreatic, and hepatobiliary cancers). We further summarize preclinical studies and clinical trials evaluating therapeutic strategies targeting tCDKs, including small-molecule inhibitors, degraders, and genetic approaches, in GI tumors. Finally, we highlight key knowledge gaps and challenges in targeting tCDKs and suggest novel strategies to disrupt tCDK function, including rational drug combinations and their effects on antitumor immunity.

Transcription-associated cyclin-dependent kinases (tCDKs) precisely control the gene transcription process (initiation, elongation, and termination) by mediating RNA polymerase II phosphorylation. In several cancers, disrupted transcriptional control is emerging as a hallmark. In this review we summarize research studies of tCDKs’ role in gastrointestinal (GI) tumors, particularly, in the biology of esophageal, gastric, pancreatic, and hepatobiliary cancers. Across these tumor types, tCDKs are implicated as activators of super enhancer (SE) regions and contribute to the “transcriptional addiction” that not only drives cancer cell growth but is also attributed to therapeutic vulnerabilities. Overall, expression of tCDKs is increased in GI tumor tissues, indicating a rational target for therapeutics. We further describe emerging approaches, including genetic manipulation, small-molecule inhibitors or targeted protein degradation that disrupt tCDK functions in GI malignancies. We conclude by describing key challenges in targeting tCDKs and future treatment directions.