Abstract 3785: Olaparib increases the effectiveness of radiation in hypoxic tumor cells in xenograft models of human non-small-cell lung cancer

Purpose: Poly (ADP-ribose) polymerase (PARP) detects DNA single strand breaks and facilitates their repair. Recently, PARP inhibitors have been shown to potentiate radiotherapy in mouse models of human non-small-cell lung cancer (NSCLC) by compromising DNA repair and increasing tumor vascular perfusion. This study examined radiosensitization by PARP inhibition in xenograft models of NSCLC with differing levels of hypoxia. Methods: For in vitro studies, human NSCLC cell lines Calu-6 and Calu-3 were treated with olaparib (5 µM) or vehicle prior to ionizing radiation (IR). Cytotoxicity was evaluated by clonogenic survival assays and DNA damage repair was assessed by γH2AX foci immunofluorescence staining. For in vivo efficacy studies, Calu-6 or Calu-3 subcutaneous xenografts (100 mm3) were established in 6-8 week old female BALB/c nude mice. Animals (n=48) were then randomized into four groups (i) control, (ii) olaparib (50 mg/kg, d1-3), (iii) IR (10 Gy, d1) and (iv) combination treatment. Subsequent tumor growth was monitored for up to 42 days. In parallel, for pharmacodynamic studies, tumor bearing animals were sacrificed 24h and 72h after treatment (n=3 for each treatment and time point). Tumor sections were evaluated by immunohistochemistry (IHC). Results: In vitro, both NSCLC cell lines were significantly radiosensitized by olaparib. Sensitization enhancement ratios were 1.9 (Calu-6) and 2.2 (Calu-3). Furthermore, olaparib markedly inhibited DNA damage repair in both Calu-6 and Calu-3 cells 24h post-IR (p Conclusion: Our data identify a novel mechanism that contributes to radiosensitization by PARP inhibition in NSCLC. Olaparib selectively increased DNA damage and apoptosis in radioresistant hypoxic tumor cells with decreased HR potential. Our data also suggest that tumor hypoxia may be a potential biomarker of differential benefit from the combination of olaparib with radiotherapy. Citation Format: Yanyan Jiang, Tom Verbiest, Aoife M. Devery, Sivan M. Bokobza, Anika M. Weber, Anderson J. Ryan. Olaparib increases the effectiveness of radiation in hypoxic tumor cells in xenograft models of human non-small-cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3785. doi:10.1158/1538-7445.AM2014-3785