Do CDK4/6 inhibitors have potential as targeted therapeutics for squamous cell cancers?
Nene N Kalu1, Faye M Johnson1,2
1a Department of Thoracic/Head & Neck Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
Abstract:
Introduction Dysregulation of cell cycle progression has an established link to neoplasia and cancer progression. Components of the cyclin D-CDK4/6-INK4-Rb pathway are frequently altered in squamous cell carcinomas (SCCs) by diverse mechanisms, including viral oncogene-induced degradation, mutation, deletion, and amplification. Activation of the CDK4/6 pathway may predict response to CDK4/6 inhibitors and provide clinical biomarkers. Recently, the CDK4/6 inhibitor palbociclib showed clinical efficacy in combination with cetuximab in HNSCC patients. Areas covered This review focuses on the current research on the use of CDK4/6 inhibitors, comprising preclinical animal studies through phase II clinical trials across all SCCs. Expert opinion CDK4/6 inhibitors have a proven clinical benefit in breast cancer, but data on SCCs are sparse. Although frequent dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway in SCCs suggests that targeting CDK4/6 may hold promise for improved clinical outcomes, single-agent activity has been modest in preclinical studies and absent in clinical studies. Combinations with immunotherapy or inhibitors of the PI3 K/mTOR or EGFR pathway may be effective. Given that SCCs caused by human papillomavirus have high levels of p16 and low levels of Rb, the CDK4/6 inhibitors are predicted to be ineffective in these cancers.
Insights
CDK4/6 inhibitors show promise for squamous cell carcinomas (SCCs) by targeting cell cycle dysregulation. However, single-agent efficacy is limited in SCCs, suggesting combination therapies may be more effective.
Area of Science:
- Oncology
- Cell Biology
- Cancer Therapeutics
Background:
- Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway is common in squamous cell carcinomas (SCCs).
- CDK4/6 inhibitors have demonstrated efficacy in breast cancer, but their role in SCCs is less established.
- The combination of palbociclib and cetuximab has shown recent clinical efficacy in head and neck SCC (HNSCC).
Purpose of the Study:
- To review current research on CDK4/6 inhibitors in SCCs, from preclinical studies to Phase II clinical trials.
- To evaluate the potential of CDK4/6 pathway activation as a biomarker for treatment response.
- To explore potential combination strategies for enhancing the efficacy of CDK4/6 inhibitors in SCCs.
Main Methods:
- Review of preclinical animal studies and Phase II clinical trials involving CDK4/6 inhibitors across various SCCs.
- Analysis of mechanisms of cyclin D-CDK4/6-INK4-Rb pathway alterations in SCCs.
- Evaluation of clinical data on palbociclib in combination with cetuximab in HNSCC.
Main Results:
- Single-agent activity of CDK4/6 inhibitors has been modest in preclinical studies and absent in clinical trials for SCCs.
- Frequent alterations in the cyclin D-CDK4/6-INK4-Rb pathway suggest potential therapeutic benefit.
- CDK4/6 inhibitors are predicted to be ineffective in human papillomavirus-driven SCCs due to specific molecular profiles (high p16, low Rb).
Conclusions:
- While CDK4/6 inhibitors have proven benefit in breast cancer, their efficacy as single agents in SCCs is limited.
- Combination therapies, potentially with immunotherapy or inhibitors of PI3K/mTOR or EGFR pathways, may enhance outcomes in SCCs.
- Patient selection is crucial, as HPV-associated SCCs may not benefit from CDK4/6 inhibition.
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