Inhibition of CD4/CDK6 enhances radiosensitivity of HPV negative head and neck squamous cell carcinomas.
Göttgens E-L., Bussink J., Leszczynska KB., Peters H., Span PN., Hammond EM.
PURPOSE: Human papillomavirus negative (HPV-ve) head and neck squamous cell carcinomas (HNSCC) have a poor prognosis compared to HPV+ve HNSCCs. Expression of p16 in HPV+ve HNSCC is thought to mediate radiosensitivity via inhibition of cyclin-dependent kinase (CDK) 4/6. We used a clinically approved CDK4/CDK6 inhibitor, palbociclib, and assessed its effect on radiosensitivity in HNSCC. METHODS AND MATERIALS: The effect of palbociclib on radiosensitivity was determined in HPV-ve and +ve HNSCC cell lines using colony survival assays, immunofluorescent staining of repair proteins, homologous recombination (HR) assays, cell cycle and metaphase spread analyses. RESULTS: Only HPV-ve HNSCC cells were radiosensitized by palbociclib, which also occurred at hypoxic levels associated with radioresistance. Palbociclib led to a decreased induction of BRCA1 and RAD51 after irradiation. HR was diminished and repair of radiation-induced DNA damage was delayed in the presence of palbociclib leading to increased chromosomal damage. Failure to repair radiation-induced damage led to cell death as a result of mitotic catastrophe. CONCLUSIONS: Here, we highlight a therapeutic strategy to improve the radiosensitivity of HPV-ve HNSCC, a patient group that has an unmet and urgent need for improved radiotherapy efficacy.