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

Patients with human papillomavirus type 16 (HPV)-associated oropharyngealsquamous cell carcinomas (OPSCC) display increased sensitivity to radiotherapy andimproved survival rates in comparison to HPV-negative forms of the disease. Howeverthe cellular mechanisms responsible for this characteristic difference are unclear.Here, we have investigated the contribution of DNA damage repair pathways to thein vitro radiosensitivity of OPSCC cell lines. We demonstrate that two HPV-positiveOPSCC cells are indeed more radiosensitive than two HPV-negative OPSCC cells, whichcorrelates with reduced efficiency for the repair of ionising radiation (IR)-inducedDNA double strand breaks (DSB). Interestingly, we show that HPV-positive OPSCCcells 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 strandbreak (SSB) repair. This translates to an increased capacity and efficiency for therepair of DNA base damage and SSBs in these cells. In addition, we demonstratethat HPV-positive but interestingly more so HPV-negative OPSCC display increasedradiosensitivity in combination with the PARP inhibitor olaparib. This suggests thatPARP inhibition in combination with radiotherapy may be an effective treatmentfor both forms of OPSCC, particularly for HPV-negative OPSCC which is relativelyradioresistant