Disturbed DNA repair in HPV-associated head and neck cancer: underlying mechanisms and clinical applications

Postdoc Assoc Surg Otolaryng
800 Howard Ave, New Haven, CT 06519-1369

Head and neck cancer is the sixth most common cancer worldwide, with the prevalent histology being squamous cell carcinoma (SSC). Several reports have connected oropharyngeal SCC (OPSCC) with human papillomavirus (HPV) infection; it is estimated that about 60% of OPSCCs are HPV-positive (HPV+). More than 80% of HPV+ OPSCC patients are curable with concurrent radiation and cisplatin-based chemotherapy. In contrast, HPV- OPSCC are resistant to identical treatment with cure rates far below 50%.  Clear mechanisms, explaining differences in therapeutic response and survival between HPV+ and HPV- OPSCC patients, have not been forthcoming. Despite an improved survival rate of HPV+ patients, treatment-related side effects remain severe; therefore, clinical interest in de-escalation of therapy and/or discovery of novel therapeutic targets in OPSCC and biomarkers predicting response is extremely high.

Our data suggest that, as a class, HPV+ OPSCC contained elevated levels of endogenous DNA single strand breaks (SSBs) and harbored overexpressed and overactive SSBs repair proteins, including PARP-1. Moreover, HPV+ cells were more prone to the formation of DNA double strand breaks (DSBs) in response to the treatment with replication inhibitor hydroxyurea (HU) and continued to rapidly accumulate DSBs after release from HU. Further studies revealed that HPV+ cells were sensitive to the inhibition of SSBs repair, including PARP inhibitors treatment. Mechanistically, we found that HPV+ head and neck cancer cells and tumors express high levels of HPV E2 protein. Depletion of E2 with siRNA resulted in downregulation of PARP-1 and decreased levels of endogenous SSBs.

We discuss underlying mechanisms and therapeutic applications of the phenotype observed in HPV+ OPSCC.