title: 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.
authors.affiliation: a Department of Thoracic/Head & Neck Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Nene N
authors.initials: NN
authors.lastname: Kalu
authors.affiliation: a Department of Thoracic/Head & Neck Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.|b The University of Texas Graduate School of Biomedical Sciences , Houston , TX , USA.
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D018450:Disease Progression; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6
keywords: CDK4; CDK4/6 inhibitors; CDK6; anogenital cancers; cervical cancer; head and neck cancer; lung cancer; squamous cell carcinoma