Do CDK4/6 inhibitors have potential as targeted therapeutics for squamous cell cancers?

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.

KEYWORDS:

• CDK4
• CDK6
• squamous cell carcinoma
• lung cancer
• head and neck cancer
• cervical cancer
• anogenital cancers
• CDK4/6 inhibitors

Article highlights

• Genomic alterations in the cyclin D-CDK4/6-INK4-Rb pathway frequently occur inSCCs.

• Preclinical and clinical studies of CDK4/6 inhibitors in SCCs are few, but have failed todemonstrate significant efficacy in biomarker-unselected patients and preclinical models.

• Recent studies in head and neck squamous cell carcinomas (HNSCC) show efficacy ofCDK4/6 inhibitors in vitro and in vivo in combination with EGFR and mTOR inhibitors.

• No current biomarkers of response to CDK4/6 inhibitors have been established in SCCbut CDK4/6, CCND1, CCND2, and CCND3 are currently being tested prospectively in aclinical trial in lung SCC.

• Ongoing clinical trials in lung SCC and HNSCC will provide crucial information on thepotential use of CDK 4/6 inhibitors as targeted therapy for SCCs in the future.

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to acknowledge the scientific editing assistance of Kate Hale from MD Anderson Cancer Center.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.