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Development of an Orally Bioavailable CDK12/13 Degrader and Induction of Synthetic Lethality with AKT Pathway Inhibition - Beyond the Abstract

Advanced prostate cancer, particularly metastatic castration-resistant prostate cancer (mCRPC), remains one of the most challenging malignancies to treat. While androgen-deprivation therapies and next-generation antiandrogens provide initial tumor control, resistance inevitably develops, highlighting the critical need for novel therapeutic strategies. Our recent study addressed this gap by focusing on cyclin-dependent kinases 12 and 13 (CDK12/13), essential regulators of transcription elongation, DNA damage response, and genomic stability.1

In this work, we developed YJ1206, the first orally bioavailable CDK12/13 degrader using the proteolysis-targeting chimera (PROTAC) approach. YJ1206 induced robust tumor regression in preclinical models, including both cell-derived mCRPC and patient-derived xenografts (PDXs), without significant side effects. YJ1206 also exhibited no signs of toxicity following prolonged treatment in immune-competent CD-1 mice. Mechanistically, CDK12/13 degradation triggered transcriptional elongation defects, preferentially disrupting the expression of long genes critical for DNA repair.

This led to the accumulation of DNA damage, cell cycle arrest, and ultimately cancer cell death. Notably, in a companion manuscript published in the same issue of Cell Reports Medicine,2 we demonstrated that degradation of CDK13 in the setting of CDK12 loss represents a promising therapeutic avenue.

Our study also uncovered a compelling interplay between CDK12/13 degradation and the AKT signaling pathway. Degrading CDK12/13 upregulated AKT phosphorylation, likely as a compensatory response to DNA damage-induced stress. This finding provided a rationale for combining YJ1206 with the AKT inhibitor uprosertib. The combination therapy exhibited a striking synergistic effect, achieving near-complete tumor regression in both mCRPC and PDX models. The combination regimen was also well tolerated with no signs of toxicity. Importantly, these results suggest that dual targeting of CDK12/13 and AKT pathways may overcome resistance mechanisms commonly observed in aggressive prostate cancers.

Beyond demonstrating the efficacy of YJ1206, our work underscores the potential of precision medicine approaches that exploit synthetic lethality and pathway vulnerabilities. The promising preclinical results of YJ1206, particularly in combination with AKT inhibitors, offer a new avenue for addressing the unmet needs of patients with therapy-resistant prostate cancer. As we progress toward clinical trials, our findings pave the way for combination regimens that integrate transcriptional and signaling pathway inhibitors, potentially redefining treatment paradigms for aggressive cancers.

Written by: Xiaoju Wang,1,2,3 Stephanie J. Miner,1,2 Ke Ding,4 and Arul M. Chinnaiyan1,2,3,5,6

  1. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
  2. Department of Pathology, University of Michigan, Ann Arbor, MI, USA
  3. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
  4. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, People’s Republic of China
  5. Department of Urology, University of Michigan, Ann Arbor, MI, USA
  6. Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA
References:

  1. 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.
  2. 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. 
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