How selective are clinical CDK4/6 inhibitors?
Denisa Hendrychová1, Radek Jorda1, Vladimír Kryštof1
1Department of Experimental Biology, Faculty of Science, Palacký University, Olomouc, Czech Republic.
Abstract:
Pharmacological inhibition of cyclin-dependent kinase 4/6 (CDK4/6) has emerged as an efficient approach for treating breast cancer, and its clinical potential is expanding to other cancers. CDK4/6 inhibitors were originally believed to act by arresting proliferation in the G1 phase, but it is gradually becoming clear that the cellular response to these compounds is far more complex than this. Multiple context-dependent mechanisms of action are emerging, involving modulation of quiescence, senescence, autophagy, cellular metabolism, and enhanced tumor cell immunogenicity. These mechanisms may be driven by interactions with unexpected targets. We review cellular responses to the Food and Drug Administration-approved CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib, and summarize available knowledge of other drugs undergoing clinical trials, including data on their off-target landscapes. We emphasize the importance of comprehensively characterizing drugs' selectivity profiles to maximize their clinical efficacy and safety and to facilitate their repurposing to treat additional diseases based on their target spectrum.
Insights
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors show complex cellular responses beyond G1 arrest in cancer treatment. Understanding these mechanisms and off-target effects is crucial for maximizing efficacy and safety.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are effective in breast cancer and expanding to other malignancies.
- Initial understanding of CDK4/6 inhibitors focused on G1 cell cycle arrest.
- Emerging evidence reveals more complex cellular responses to CDK4/6 inhibition.
Purpose of the Study:
- To review the multifaceted cellular responses to FDA-approved CDK4/6 inhibitors.
- To summarize the mechanisms of action beyond G1 arrest.
- To explore the off-target landscape of CDK4/6 inhibitors in clinical trials.
Main Methods:
- Literature review of cellular responses to palbociclib, ribociclib, and abemaciclib.
- Analysis of emerging mechanisms including quiescence, senescence, autophagy, metabolism, and immunogenicity.
- Compilation of data on off-target effects of drugs in clinical trials.
Main Results:
- CDK4/6 inhibitors induce complex cellular responses, including modulation of quiescence, senescence, autophagy, metabolism, and tumor immunogenicity.
- These effects can be driven by interactions with unexpected targets.
- Off-target profiles of investigational CDK4/6 inhibitors are being characterized.
Conclusions:
- The cellular response to CDK4/6 inhibitors is more complex than previously thought.
- Comprehensive characterization of drug selectivity is vital for optimizing clinical efficacy and safety.
- Understanding off-target effects can facilitate drug repurposing for other diseases.
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