Abstract A118: The PARP1 inhibitor olaparib (AZD2281) enhances radiation-induced DNA damage in BRCA1/BRCA2 wild-type head and neck squamous cell carcinoma cell lines

Abstract

Abstract Introduction: In 2008, there were approximately 65,000 cases of head and neck cancer diagnosed in the United States, with over 500,000 cases worldwide. For many patients with locally advanced disease, multiple treatment modalities are combined and typically include radiotherapy, which induces DNA damage in tumor cells. Poly (ADP-ribose) polymerase 1 (PARP1) is involved in maintenance of genome integrity, and functions as a key mediator of DNA repair. The objective of this study was to determine if combining the PARP1 inhibitor olaparib (AZD2281) with radiation in head and neck squamous cell carcinoma (HNSCC) cell lines results in enhanced DNA damage and cell death. Materials and Methods: The effects of olaparib and radiation were assessed in the BRCA1/BRCA2 wild-type HNSCC cell lines UMSCC2, HN31, MDA-584, and UMSCC25. DNA damage following treatment was determined 2 hours post-radiation by immunofluorescence and flow cytometry using γ-H2A.X-Alexa488 conjugated antibodies. Single cell electrophoresis (comet assay) 24 hours post-radiation was used to measure DNA fragmentation, and long-term cell survival was evaluated by clonogenic survival. Results: In all cell lines tested, both radiation and olaparib alone induced DNA damage as measured by γ-H2A.X foci formation, and the combination of olaparib and radiation significantly enhanced this response. DNA fragmentation was also greater in combination treatments, and this lead to a lower clonogenic survival for all cell lines. Conclusions. The combination the PARP inhibitor olaparib with radiation enhanced DNA damage in HNSCC cell lines and lead to greater cell death. This study demonstrated that PARP1 inhibition combined with a DNA damaging agent such as radiation was effective in inhibiting growth of BRCA1/BRCA2 wild-type cell lines. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A118.