Abstract 1460: Comparison of radiosensitizing effects of several PARP inhibitors under clinical investigation

Abstract Targeting tumor DNA repair is an attractive strategy in selectively killing tumors while sparing normal tissues. Inhibiting Poly (ADP-ribose) polymerase (PARP) in cancers with BRCA1 and BRCA2 mutations has been shown to be a promising approach either as a single agent or in combination therapy with chemotherapeutics or ionizing radiation. To systematically compare the radiosensitizing efficacy of various PARP inhibitors we have evaluated the long-term cytotoxicity of ABT-888, AZD2281, MK4827, and BSI-201 in clonogenic survival assays in combination with ionizing radiation. For these studies we used the breast cancer cell lines MDA-MB 231 BR, a subline of MDA-MB-231 selected for its tendency to metastasize to brain (BRCA1+/−) and MX-1 (BRCA1 deletion and BRCA2 mutation). Furthermore, we have evaluated PARP inhibitors under normoxic and hypoxic conditions (21% O2 versus 0.1% O2). In MDA-MB 231 BR cells, at a clinically relevant and achievable concentration for ABT-888 (J Clin Oncol. 2009; 27(16)) and AZD2281(N Engl J Med. 2009; 361(2)), and at 1 uM MK4827 showed radiosensitizing effects under both normoxic and hypoxic conditions. BSI-201 at a clinically achievable concentration (ASCO 2010, Abstract 2012) did not exhibit radiosensitizing effects under the same conditions. When MX-1 cells were treated with BSI-201 under hypoxic conditions (0.1% O2) the cytotoxicity of BSI-201 was evident. Taken together, the results show that ABT-888, AZD2281 and MK4827 show promising radiosensitizing effects under both normoxic and hypoxic conditions whereas the cytotoxicity of BSI-201 was observed only under hypoxic conditions in BRCA1/2 mutant carrier MX-1cells. 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 1460. doi:1538-7445.AM2012-1460