Targeting replication stress and homologous recombination repair mechanisms in HPV-positive and negative head and neck cancer

Abstract Head and Neck squamous cell carcinoma (HNSCC) is the seventh most common cancer world-wide and afflicts more than 50,000 individuals in the U.S. each year. Because of its anatomic location and poor survival rate HNSCC is a devastating disease. Treatment can lead to profound functional defects and disfigurement. In the U.S., HNSCC incidence is increasing in large part due to the human papillomavirus (HPV). Although HPV- driven HNSCC generally has a better outcome than its HPV-negative counterpart, smokers with HPV-driven HNSCC demonstrate inferior oncologic outcomes and are clinically defined as intermediate risk disease. The significant complexity of HNSCC biology results in a complex clinical scenario, in which some patients are overtreated while others are undertreated, leading to unnecessary long-term side effects and suboptimal clinical response. In the laboratory, we discovered that HPV+ HNSCCs have unusually high expression of genes involved in DNA damage and repair (DDR) and are highly sensitive to drugs targeting RAD51, a DDR protein functioning in homologous recombination repair (HRR) that also protects cells from replication stress (RS). We hypothesize that the HPV-driven biology of this genomic subset of HNSCC renders them more sensitive to drugs targeting RS and HRR. We further hypothesize that HPV-neg HNSCC that share the same pattern of overexpressed DDR genes may also be susceptible to drugs targeting RS/HRR. In this translational proposal, we plan to: 1) Determine the efficacy and feasibility of replacing cisplatin with a RAD51 inhibitor to sensitize tumors to radiation using preclinical models of HPV+ HNSCC; 2) Elucidate the molecular mechanisms governing sensitivity of HPV+HNSCC to RAD51 inhibition; 3) Determine if drug combinations targeting RS or HRR are efficacious in preclinical models of HNSCC. Progress in this area could lead directly to human clinical trials that may improve tumor control with less toxicity.