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PURPOSE: Human papillomavirus negative (HPV-ve) head and neck squamous cell carcinoma (HNSCC) has a poor prognosis compared with 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 HPV+ve HNSCC cell lines using colony survival assays, immunofluorescent staining of repair proteins, homologous recombination 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 decreased induction of BRCA1 and RAD51 after irradiation. Homologous recombination 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 radiation therapy efficacy.

Original publication

DOI

10.1016/j.ijrobp.2019.06.2531

Type

Journal article

Journal

Int J Radiat Oncol Biol Phys

Publication Date

01/11/2019

Volume

105

Pages

548 - 558

Keywords

BRCA1 Protein, Cell Cycle, Cell Death, Cell Line, Tumor, Chromosome Aberrations, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin-Dependent Kinase Inhibitor p16, DNA Repair, DNA-Binding Proteins, Head and Neck Neoplasms, Homologous Recombination, Humans, Neoplasm Proteins, Papillomaviridae, Phosphorylation, Piperazines, Protein Kinase Inhibitors, Pyridines, Rad51 Recombinase, Radiation Tolerance, Radiation-Sensitizing Agents, Retinoblastoma Protein, Squamous Cell Carcinoma of Head and Neck, Tumor Hypoxia, Tumor Stem Cell Assay