Abstract 5496: Cetuximab induces synthetic lethality with the poly (ADP-Ribose) polymerase (PARP) inhibitor ABT-888 in head and neck cancer

Abstract

Abstract Purpose: Overexpression/amplification of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab, almost half of treated patients fail this therapy. PARP inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing homologous recombination (HR)-deficient tumors while maintaining minimal toxicity in normal tissues. As EGFR inhibition has been reported to alter cellular DNA repair capacity, we investigated whether cetuximab could induce a transient DNA repair deficit and subsequently induce a synthetic lethality with the PARPi ABT-888 in head and neck cancer cells. Methods: The head and neck cancer cell lines UM-SCC1, UM-SCC6, and FaDu were used in this study. Kinetics of DNA damage and repair were assessed by immunofluorescence staining of cells for γ-H2AX, Rad51, and DNA-Pk foci at various time points following irradiation (IR). Cell viability was determined via the ATPlite as well as colony formation assays. Apoptosis was evaluated by Annexin V staining as well as cleaved caspase 3 and 9 levels. Cell cycle analysis was performed via flow cytometry. Results: Cetuximab increases γ-H2AX foci, which are well established markers of DNA double strand breaks (DSBs), in head and neck tumor cells. This coincides with reduced DSB-repair as indicated by attenuation of IR-induced Rad51 and DNA-Pk foci, which are well characterized in situ markers of the homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA repair pathways, respectively. Importantly, cetuximab induces synthetic lethality with the PARPi ABT-888 through a mechanism involving persistent DNA damage and subsequent activation of the intrinsic pathway of apoptosis. The observed effects are not due to cell cycle redistribution. Conclusions: By generating a DSB repair deficiency, cetuximab can render head and neck tumor cells susceptible to PARP inhibition. The combination of cetuximab and the PARPi ABT-888 can thus be an innovative treatment strategy to enhance therapeutic ratio and improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5496. doi:10.1158/1538-7445.AM2011-5496