Abstract
Transcriptional addiction describes the dependence of cancer cells on sustained RNA polymerase II (Pol II)-driven gene expression to maintain short-lived survival proteins, including MYC and MCL-1 (myeloid cell leukemia-1). Cyclin-dependent kinase 9 (CDK9), the catalytic kinase within the positive transcription elongation factor b (P-TEFb), controls the transition from promoter-proximal pausing to productive transcriptional elongation and is therefore a central vulnerability in tumors driven by amplified oncogenic transcription. This review provides a comprehensive translational survey of the CDK9-targeting landscape, spanning biology, inhibition, and protein degradation. It is organized around the thesis that targeted CDK9 protein degradation represents the most mechanistically complete strategy for disrupting transcriptional addiction in cancer. Although kinase inhibitors established proof of concept, their effects can be limited by transient target suppression, compensatory pathway reactivation, and incomplete disruption of non-catalytic CDK9 functions. Targeted protein degraders offer a mechanistically distinct approach by eliminating the CDK9 protein pool and suppressing both catalytic and scaffold functions. Combination strategies targeting anti-apoptotic proteins, bromodomain readers, and DNA damage response pathways may further exploit transcriptional vulnerabilities, positioning CDK9-directed protein degradation as a mechanistically grounded framework for precision oncology in both hematological and solid tumors.