A High Throughput Cell-based Screen Identifies Compounds That Inhibit the Viral Oncoprotein E6 in Human Papillomavirus-positive Cancers

previously demonstrated attenuation of DNA repair capacity in HERinhibited cells. We thus hypothesized that erlotinib, a tyrosine kinase inhibitor which suppresses HER1/HER2 signaling, could induce a transient DNA repair deficit and subsequently induce synthetic lethality with the PARPi ABT-888 in esophageal cancer cells. Materials/Methods: Esophageal cancer cell lines, including squamous cell carcinoma (SCC, KYSE-30) and adenocarcinoma (adenoCa, OE-33) cells, were used in this study. Erlotinib, a tyrosine kinase inhibitor, and ABT-888, a PARP1/2 inhibitor were used in this study. DNA damage and repair were assessed by immunofluorescence staining of cells for gH2AX and Rad51 foci. Cell viability was determined via cell proliferation assays. Results: Consistent with our hypotheses, erlotinib increased g-H2AX foci, a marker of DNA double strand breaks (DSBs), in esophageal SCC tumor cells. This coincided with reduced DSB-repair capacity as assessed via RAD51 foci. Esophageal SCC cells demonstrated no cytotoxicity with either agent alone (0.1-0.5 uM erlotinib and 1-10 uM ABT888), however a synthetic lethal relationship was observed with the combination treatment (50% decrease, p < 0.05). Surprisingly, esophageal adenoCa cells were sensitive to the PARPi, ABT-888, alone (45% decrease, p < 0.05). Conclusions: Thus, the combination of erlotinib and PARPi or the PARPi alone can be an innovative treatment strategy to enhance the therapeutic ratio and improve outcomes in esophageal SCC or adenocarcinoma cancer patients, respectively. Additional studies will be necessary to determine the mechanism by which adenoCa cells are sensitive to PARPi alone. Furthermore, this strategy may also be feasible for other HER overexpressing tumors, including lung, breast and brain cancers. Acknowledgment: This project is supported by the Bo Johnson Memorial Foundation. Author Disclosure: A.C. Whitley: None. J. Jackson: None. H. Trummell: None. J. Bonner: None. E.S. Yang: None.