The evolving landscape of CDK2 inhibition in cancer: Therapeutic potential, clinical progress, and future directions
Jimma Likisa Lenjisa1, Sara Kasirzadeh1, Ava Safaroghli-Azar1
1Drug Discovery and Development, School of Pharmacy and Biomedical Sciences, College of Health, Adelaide University, Adelaide, SA 5001, Australia.
Abstract:
Cyclin-dependent kinase 2 (CDK2) is a central orchestrator of G1/S and G2/M cell cycle progression. Its aberrant activation drives cancer progression in various malignancies, making CDK2 inhibition a promising therapeutic prospect. However, high structural similarity between CDK2 and family members like CDK1 and CDK5 has made discovering selective inhibitors with desirable safety and efficacy a two-decade-long challenge. CDK2 drives oncogenesis primarily in Cyclin E1 (CCNE1)-amplified and p16-high tumors. Furthermore, aberrant CDK2 signaling facilitates resistance against diverse chemotherapies and targeted agents, most significantly CDK4/6 inhibitors. While dispensable for most normal cells, CDK2 can be activated as a mediator of renal and cardiovascular toxicity during chemotherapy. Emerging evidence also identifies a novel immunomodulatory role for CDK2, where its inhibition may potentiate immune checkpoint blockade. Recently, multiple selective CDK2 inhibitors have entered clinical trials, showing promising early signals of efficacy and safety. This review provides a comprehensive and up-to-date synthesis of the multifaceted roles of CDK2 in cancer, examining the landscape of selective CDK2 inhibitors and next-generation degraders (PROTACs/Molecular Glues) currently in clinical pipelines. We critically analyze translational hurdles-including the quest for super-selectivity over CDK1, the validation of predictive biomarkers, and resistance mapping-to provide a strategic direction for the future of CDK2-based cancer therapeutics.
Insights
Cyclin-dependent kinase 2 (CDK2) inhibition shows promise for cancer therapy by targeting cell cycle progression. Developing selective CDK2 inhibitors faces challenges due to structural similarities with related kinases, but new agents are advancing in clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cyclin-dependent kinase 2 (CDK2) is crucial for cell cycle regulation (G1/S and G2/M phases).
- Aberrant CDK2 activation contributes to cancer progression and chemoresistance.
- CDK2 shares structural similarity with CDK1 and CDK5, complicating selective inhibitor development.
Purpose of the Study:
- To review the diverse roles of CDK2 in cancer.
- To examine the current landscape of selective CDK2 inhibitors and novel degraders (PROTACs/Molecular Glues).
- To analyze translational challenges and strategic directions for CDK2-based cancer therapeutics.
Main Methods:
- Comprehensive literature review of CDK2's role in oncogenesis and therapeutic strategies.
- Analysis of clinical trial data for selective CDK2 inhibitors and degraders.
- Critical evaluation of translational hurdles, including selectivity, biomarkers, and resistance.
Main Results:
- CDK2 drives oncogenesis in specific tumor types (e.g., CCNE1-amplified, p16-high).
- CDK2 inhibition may overcome resistance to existing therapies and potentiate immunotherapy.
- Emerging selective CDK2 inhibitors show early promise in clinical trials.
Conclusions:
- Selective CDK2 inhibition represents a promising therapeutic strategy for various cancers.
- Overcoming challenges in selectivity, biomarker validation, and resistance mapping is key for clinical success.
- Next-generation CDK2 inhibitors and degraders are advancing, offering new hope for patients.
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