Abstract 2548: Chemosensitization of cancer cells by KU-0060648: A dual inhibitor of DNA-PK and PI-3K

Abstract

Abstract DNA double strand breaks (DSBs) are the most cytotoxic lesions induced by topoisomerase II poisons. Enzyme-mediated repair of DNA DSBs is a major mechanism of resistance to DNA DSB-inducing agents. Non-homologous end joining (NHEJ) is the major pathway for the repair of DSBs and requires DNA-PK activity. DNA-PK has close structural similarities to PI-3K, which promotes cell survival and proliferation and is up-regulated in many cancers. KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. We investigated the therapeutic utility of KU-0060648, in models of human cancer. KU-0060648 was investigated in a panel of human breast and colon cancer cells, it inhibited cellular DNA-PK auto-phosphorylation with IC50 values of 0.019 µM (MCF7 cells) and 0.17 µM (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC50 values of 0.039 µM (MCF7 cells) and >10 µM (SW620 cells). 5-day exposure to 1 µM KU-0060648 inhibited cell proliferation by > 95% in MCF7 cells, but only by 55% in SW620 cells. In clonogenic survival assays, KU-0060648 increased the cytotoxicity of etoposide and doxorubicin across the panel of DNA-PKcs-proficient cells, but not in DNA-PKcs-deficient cells, thus confirming that enhanced cytotoxicity was due to DNA-PK inhibition. In mice bearing SW620 and MCF7 xenografts, concentrations of KU-0060648 that were sufficient for in vitro growth inhibition and chemosensitisation were maintained within the tumour for at least 4 hours at non-toxic doses. KU-0060648 alone delayed the growth of MCF7 xenografts and increased etoposide-induced tumour growth delay in both SW620 and MCF7 xenografts by up to 4.5-fold, without exacerbating etoposide toxicity to unacceptable levels. The proof of principle in vitro and in vivo chemosensitisation with KU-0060648 justifies further evaluation and characterisation of dual DNA-PK and PI-3K inhibitors. 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 2548. doi:10.1158/1538-7445.AM2011-2548