DNA Damage Signaling is a Biomarker and Target for Therapy in Human Papillomavirus Oropharyngeal Cancer

Head and neck cancer (HNC) is a common form of cancer seen worldwide. There are estimates of more than 600,000 cases per year. In the US, the prevalence of oral HPV infection has steadily risen. The human papillomavirus has been linked with increasing incidence of oropharyngeal cancer. HPV is known to infect the basal cells of stratified epithelia. HPV accesses this tissue through breaks within the mucosa. The proteins E6 and E7 are high risk associated HPV proteins that bind to p53 and Rb tumor suppressors. This causes the degradation of these proteins which allows for increased cell cycle progression. HPV replication can activate the DNA damage response. HPV can activate the ataxia telangiectasia mutated (ATM) protein. This causes phosphorylation of multiple downstream protein targets such as checkpoint kinase 2 (Chk2). In order for HPV to replicate, ATM activation is required. Double stranded breaks in DNA cause activation of ATM. This may be caused by HPV replication stress. This study demonstrated that ATM activation as well as double strand DNA breaks are significantly correlated with HPV+ oropharyngeal cancers. Due to the importance of ATM activation for proper HPV replication, we hypothesized that the inhibition of the ATM protein may be useful as a drug therapy target for HPV+ oropharyngeal cancers. ATM inhibition was found to increase the amount of double strand DNA breaks at replication foci in HNC cell lines. The inhibition of ATM was found to block the cell cycle progression at G2/M phase. This inhibition also was shown to alter the regulatory protein expression seen with in the cell cycle which causes widespread apoptosis. The study showed that implanted tumors were able to produce HPV virion particles. It also showed that inhibition of ATM prevented further cancer cell growth in vivo. This was due to initiation of apoptosis. The inhibition of the E6 protein resulted in apoptosis and cell cycle inhibition in human HPV+ cancer cell lines. This model is based on double strand DNA break signaling which appears to be an important biomarker of HPV+ head and neck cancer. The goal is to therapeutically inhibit this DNA break signaling in order to improve treatment outcomes in vivo.