Inhibition of CD4/CDK6 enhances radiosensitivity of HPV negative head and neck squamous cell carcinomas

Journal article

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.

Authors: Göttgens, E; Bussink, J; Leszczynska, K; Peters, H; Span, P

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: International Journal of Radiation Oncology - Biology - Physics
• Volume: 105
• Issue: 3
• Pages: 548-558
• Publication date: 2019-07-01
• Acceptance date: 2019-06-25
• DOI: 10.1016/j.ijrobp.2019.06.2531
• EISSN: 1879-355X
• ISSN: 0360-3016
• Pmid: 31271827
• Language: English