Targeting Transcriptional Cyclin-Dependent Kinases in Cancer

Cyclin-dependent kinases (CDK) are critical regulators of cell-cycle progression and transcription, and their dysregulation is a hallmark of many cancers. While cell cycle inhibitors have transformed the treatment of certain cancer types, transcriptional CDKs (tCDK) are now gaining attention as potential therapeutic targets. tCDKs regulate essential processes, including RNA polymerase activation, transcriptional elongation, and RNA processing, making them crucial for tumor growth and survival. Targeting tCDKs offers a promising strategy, particularly in tumors reliant on enhanced transcriptional activity. Inhibitors of tCDKs have demonstrated efficacy in preclinical models by selectively targeting cancer cells while sparing normal cells. This selectivity arises from how normal and cancer cells utilize transcriptional machinery, with cancer cells often exhibiting heightened dependence on transcription for survival, known as "oncogene addiction". Despite promising results, several challenges remain, such as the lack of specificity of tCDKs inhibitors or limited understanding of their broader impact on the tumor microenvironment and immune response. Emerging therapeutic strategies, including targeted degradation of tCDKs and their associated cyclins, offer additional means to selectively target individual cyclin-CDK complexes. Future research is essential to address those issues and bring inhibitors of tCDKs into routine cancer care.