Novel insights into DNA damage repair defects in HPV-positive head and neck squamous cell carcinoma: from the molecular basis to therapeutic opportunities

The incidence of human papillomavirus (HPV) associated head and neck squamous cell carcinoma (HNSCC) has dramatically increased in recent decades. There is clear evidence in literature that patients with HPV-positive HNSCC have a significantly better prognosis after genotoxic therapies compared to those with HPV-negative HNSCC. This favorable outcome has been associated with distinct features in DNA damage repair (DDR) functions specific to HPV-positive HNSCC. As a result, weaknesses in DDR have been identified for both HPV-positive and HPV-negative HNSCC, respectively. Therefore, personalized therapy targeting the vulnerable aspects of DDR pathways based on HPV status and mutational profiles has been proposed for precise treatment of HNSCC patients. This review focuses on the most recent evidence regarding the impact of HPV on DDR pathways and the related therapeutic strategies in HNSCC. We anticipate that future translation of these discoveries into clinical practice may lead to treatment de-escalation approaches in HPV-positive HNSCC and more effective therapies for the poor prognosis HPV-negative HNSCC.