Work

Inhibition of RNA polymerase II-activating CDK9 and CDK12/13, but not of cell cycle relevant CDKs, induces apoptosis by downregulating the short-lived Bcl-2 proteins Mcl1 and Bfl1/A1

Year: 2026

Type: article

Abstract: Cyclin-dependent kinases (CDKs) play a crucial role in cell cycle (such as CDK1 and CDK4/6) and transcription (such as CDK7, CDK9, and CDK12/13). While CDK inhibitors are clinically effective in cancer therapy, their mechanisms of apoptosis induction remain incompletely understood. Here, we demonstrate that inhibition of CDKs involved in cell cycle control (such as CDK1 or CDK4/6) displays no cytotoxic potential. Surprisingly, inhibition of CDK7, which is involved in the control of cell cycle and transcriptional initiation, also showed no cytotoxicity. Only inhibition of CDK9 (by AZD4573 and atuveciclib) or of CDK12/13 (by SR4835 and THZ531)-which target the transcriptional elongation of RNA polymerase II (RNAPII)-exerted a strong apoptotic potential. Since CDK9 and CDK12/13 target different elongation factors associated with RNAPII (such as SPT6 and NELF for CDK9; CDC73, and LEO1 for CDK12/13), they cannot substitute for each other. Consequently, the combination of AZD4573 with SR4835 resulted in significant, synergistic cytotoxicity. Inhibiting CDK9 or CDK12/13 induced the rapid downregulation of the short-lived, anti-apoptotic Bcl-2 proteins Mcl1 and A1/Bfl1 in Jurkat leukemia cells and SUDHL1 lymphoma cells, whereas the expression of Bcl-2 and Bcl-xL remained unaffected. Since Mcl1 and A1 antagonize the pro-apoptotic Bcl-2 proteins Bak and Bax, apoptosis induction by AZD4573 or SR4835 was blocked in Bak- and Bax/Bak-deficient Jurkat cells and strongly reduced in Bax-deficient cells. Because Bcl-2 only inhibits Bax, but not Bak, AZD4573 and SR4835 were able to induce apoptosis in Jurkat cells overexpressing Bcl-2. As tumor cells frequently upregulate Bcl-2, inhibitors of CDK9 and CDK12/13 represent promising anticancer drugs.

Source: Cell Death and Disease

DOI: 10.1038/s41419-026-08889-6