Potential role of cyclin-dependent kinase 4/6 inhibitors in the treatment of squamous cell carcinoma of the head and neck

Abstract

Purpose of review: Human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN) is mainly driven by genetic aberrations involved in the cell cycle pathway resulting in cyclin-dependent kinase (CDK) 4 and 6 activation. This supports the investigation of the activity of CDK4/6 inhibitors in this disease. We review the therapeutic potential of CDK4/6 inhibitors in SCCHN.

Recent findings: CDK4/6 inhibitors in monotherapy have demonstrated cytostatic activity in HPV-negative SCCHN. Combination with epidermal growth factor inhibitors, with phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathways inhibitors or with immunotherapy, have shown promising preclinical efficacy. No strong predictive biomarkers of response or resistance have been firmly identified.Phase I clinical trials have demonstrated that palbociclib or ribociclib in combination with cetuximab is well tolerated. A phase II single-arm trial combining palbociclib/cetuximab has shown promising results.

Summary: Inhibition of CDK4/6 represents a new potential treatment for HPV-negative SCCHN patients. Randomized clinical trials that investigate these compounds in an unbiased manner are needed to fully evaluate their efficacy. However, it is unlikely that all the patients will benefit from this new approach. To determine a molecular profile/phenotype that will predict CDK4/6 inhibitor activity, researchers will have to take into account simultaneously occurring events in the cyclin-D/CDK4/CDK6/retinoblastoma and associated pathways.