Abstract 4684: Synthetic lethal interaction between EGFR and PARP inhibition

Abstract

Abstract Purpose: Dysregulation of the epidermal growth factor receptor (EGFR) family is a hallmark of many cancers. Although targeting of EGFR family has improved outcomes, many patients ultimately 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. We have previously shown that EGFR inhibition induces synthetic lethality with PARPi in head and neck squamous cell carcinomas (HNSCCs) in vitro by attenuating DNA repair pathways. In this study, we validated these observations in vivo in HNSCCs xenografts. Importantly, we also tested this strategy in other EGFR dysregulated cancers. Methods: Cervical, breast, and head and neck cancer cell lines were used in this study. DNA damage and repair were assessed by immunofluorescence staining of cells for γ-H2AX, Rad51, and DNA-Pk foci and/or chromosomally integrated HR and nonhomologous end-joining based GFP reporter assays. Cell viability was determined via colony formation and ATPlite assays. Tumor growth delay was assessed in mice bearing tumor xenografts. Results: Combined EGFR and PARP inhibition resulted in the greatest tumor growth delay versus either agent alone in mice bearing head and neck tumor xenografts (9 week tumor growth delay when compared to PARPi alone, 3 week tumor growth delay when compared to EGFR inhibitor alone). This correlated with persistent γ-H2AX foci indicative of unresolved DNA damage. Interestingly, this combination was also effective in other EGFR dysregulated tumors. Human cervical and breast cancer cells exhibited enhanced cytotoxicity with EGFR and PARP inhibition compared to either agent alone (80-99% cytotoxicity with combination vs 0-20% with either agent alone). Similar to head and neck cancer, susceptibility to PARPi induced by EGFR inhibition was associated with deficient NHEJ- and HR-mediated DNA repair and subsequent persistence of DNA damage. Conclusions: Thus, by generating a DNA repair deficit, EGFR inhibition can induce synthetic lethality with PARP inhibition. This can be an innovative treatment strategy for tumors with dysregulated EGFR signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4684. doi:1538-7445.AM2012-4684