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 that explored 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 also attribute 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 the functions of tCDK in GI malignancies. We conclude by describing key challenges in targeting tCDKs and future treatment directions.

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.