Treating cancer with selective CDK4/6 inhibitors
Ben O'Leary1, Richard S Finn2, Nicholas C Turner1,3
1The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
Abstract:
Uncontrolled cellular proliferation, mediated by dysregulation of the cell-cycle machinery and activation of cyclin-dependent kinases (CDKs) to promote cell-cycle progression, lies at the heart of cancer as a pathological process. Clinical implementation of first-generation, nonselective CDK inhibitors, designed to inhibit this proliferation, was originally hampered by the high risk of toxicity and lack of efficacy noted with these agents. The emergence of a new generation of selective CDK4/6 inhibitors, including ribociclib, abemaciclib and palbociclib, has enabled tumour types in which CDK4/6 has a pivotal role in the G1-to-S-phase cell-cycle transition to be targeted with improved effectiveness, and fewer adverse effects. Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge that, although unwelcome, might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response, and the use of combination therapies in order to optimize CDK4/6 targeting.
Insights
Selective cyclin-dependent kinase (CDK) 4/6 inhibitors like palbociclib show improved efficacy and safety for advanced ER-positive breast cancer. Further research is needed to overcome resistance and expand CDK4/6 inhibitor use to other cancers.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Cancer involves uncontrolled cell proliferation driven by cell-cycle machinery dysregulation.
- Early nonselective cyclin-dependent kinase (CDK) inhibitors faced toxicity and efficacy challenges.
- CDK4/6 proteins are crucial for the G1-to-S-phase cell-cycle transition.
Purpose of the Study:
- To review the clinical implementation and outcomes of selective CDK4/6 inhibitors.
- To discuss the role of CDK4/6 in cancer and the advancements in targeted therapy.
- To explore challenges and future directions for CDK4/6 inhibitor therapy.
Main Methods:
- Analysis of pivotal phase III clinical trials for CDK4/6 inhibitors.
- Review of mechanisms of action and resistance to CDK4/6 inhibitors.
- Synthesis of current literature on CDK4/6 inhibitor efficacy and safety.
Main Results:
- Selective CDK4/6 inhibitors (ribociclib, abemaciclib, palbociclib) offer improved effectiveness and reduced adverse effects.
- Palbociclib demonstrated significant progression-free survival improvement in advanced ER-positive breast cancer with good tolerability.
- Emerging mechanisms of acquired resistance to CDK4/6 inhibitors are being identified.
Conclusions:
- Selective CDK4/6 inhibitors represent a significant advancement in treating specific cancer types, notably ER-positive breast cancer.
- Overcoming acquired resistance and identifying predictive biomarkers are crucial for optimizing CDK4/6 inhibitor therapy.
- Expanding CDK4/6 inhibitor applications beyond breast cancer likely requires combination therapies and robust biomarker strategies.
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