Misregulation of DNA damage repair pathways in HPV-positive head and neck squamous cell carcinoma contributes to cellular radiosensitivity

// Catherine M. Nickson 1 , Parisa Moori 1 , Rachel J. Carter 1 , Carlos P. Rubbi 1 , Jason L. Parsons 1 1 Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L3 9TA, UK Correspondence to: Jason L. Parsons, email: j.parsons@liverpool.ac.uk Keywords: HPV, HNSCC, DNA repair, base excision repair, PARP Received: September 30, 2016      Accepted: March 08, 2017      Published: March 16, 2017 ABSTRACT Patients with human papillomavirus type 16 (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCC) display increased sensitivity to radiotherapy and improved survival rates in comparison to HPV-negative forms of the disease. However the cellular mechanisms responsible for this characteristic difference are unclear. Here, we have investigated the contribution of DNA damage repair pathways to the in vitro radiosensitivity of OPSCC cell lines. We demonstrate that two HPV-positive OPSCC cells are indeed more radiosensitive than two HPV-negative OPSCC cells, which correlates with reduced efficiency for the repair of ionising radiation (IR)-induced DNA double strand breaks (DSB). Interestingly, we show that HPV-positive OPSCC cells consequently have upregulated levels of the proteins XRCC1, DNA polymerase β, PNKP and PARP-1 which are involved in base excision repair (BER) and single strand break (SSB) repair. This translates to an increased capacity and efficiency for the repair of DNA base damage and SSBs in these cells. In addition, we demonstrate that HPV-positive but interestingly more so HPV-negative OPSCC display increased radiosensitivity in combination with the PARP inhibitor olaparib. This suggests that PARP inhibition in combination with radiotherapy may be an effective treatment for both forms of OPSCC, particularly for HPV-negative OPSCC which is relatively radioresistant.