We generated mice in which the Cdk12 gene was specifically ablated in the prostate epithelium. These animals developed high grade prostatic intraepithelial neoplasia (PIN) with DNA damage signatures and T cell predominant immune infiltration like that observed in human CDK12-mutant prostate cancer. Organoids generated from the Cdk12-null prostate exhibited basal-luminal differentiation defects and resistance to anti-androgen therapy. These organoids also possessed AR and MYC-mediated expression signatures consistent with hyper-transcription. We used this system to define the mechanism of DNA damage induced by Cdk12 loss and demonstrated that Cdk12-knockout organoids were susceptible to increased transcription-replication conflicts. Transcription-replication conflicts can arise in disease contexts when a cell attempts to replicate its DNA while simultaneously "hyper-transcribing" genes at an accelerated rate.
Cdk12 and Trp53 loss had synergistic effects on in vivo allograft tumorigenic potential, and Cdk12/Trp53 null grafts induced T cell infiltration in a syngeneic model. Conversely, Cdk12 ablation blunted prostate tumor growth in the established Pten-null prostate cancer mouse model. These results mirrored human prostate cancer—in which concomitant CDK12/TP53 inactivation is frequent, but CDK12/ PTEN inactivation is rare—and highlighted the context-specific effects of Cdk12 loss.
We further showed that pharmacologic degradation of CDK13, a CDK12 paralog, represents a viable targeted therapy in the setting of CDK12 loss. In a companion manuscript published in the same issue of Cell Reports Medicine,2 we observed AKT activation in the setting of CDK12 inhibition. We went on to demonstrate that combinatorial targeting of CDK12 and AKT effectively mitigated growth in multiple prostate cancer types. This study described the first orally bioavailable CDK12/13 degrader- a proteolysis targeting chimera (PROTAC) degrader called YJ1206. Importantly, YJ1206 exhibited a favorable safety profile in mouse models of advanced prostate cancer.
Together, these studies demonstrate that CDK12 is a tumor suppressor gene responsible for mitigating transcription-replication conflict-induced DNA damage, but it is also a viable therapeutic target in specific synthetic lethality contexts. Future plans include further refinement of orally bioavailable CDK12/13 degraders with the goal of investigating a lead candidate in clinical trials of advanced prostate cancer patients.
Art caption: CDK12/13 inactivation, represented by the jammed sewing machine, shifts normal prostate cells to malignant cells by inducing transcription-replication collisions and R-loop formation, leading to DNA damage. Illustration by Jessica Johnson (www.jessicajohnsonart.com).
Written by: Jean Ching-Yi Tien,1,2 Stephanie J. Miner,1,2 and Arul M. Chinnaiyan1,2,3,4,5
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
- Department of Urology, University of Michigan, Ann Arbor, MI, USA
- Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA
- Tien, J.C., et al., CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13. Cell Rep Med, 2024. 5(10): p. 101758.
- Chang, Y., et al., Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition. Cell Rep Med, 2024. 5(10): p. 101752.