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Lookup NU author(s): Dr Joanne Martin, Michael Batey, Dr Yan Zhao, Dr Celine CanoORCiD, Dr Michele Tavecchio, Dr Jody Barbeau, Liam Cornell, Professor Roger Griffin, Professor Herbie Newell, Professor Nicola CurtinORCiD
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DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs) is structurally similar to PI-3K, which promotes cell survival and proliferation and is upregulated in many cancers. KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. KU-0060648 was investigated in a panel of human breast and colon cancer cells. The compound inhibited cellular DNA-PK autophosphorylation with IC50 values of 0.019 μmol/L (MCF7 cells) and 0.17 μmol/L (SW620 cells), and PI-3K–mediated AKT phosphorylation with IC50 values of 0.039 μmol/L (MCF7 cells) and more than 10 μmol/L (SW620 cells). Five-day exposure to 1 μmol/L KU-0060648 inhibited cell proliferation by more than 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 chemosensitization were maintained within the tumor for at least 4 hours at nontoxic doses. KU-0060648 alone delayed the growth of MCF7 xenografts and increased etoposide-induced tumor growth delay in both in 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 chemosensitization with KU-0060648 justifies further evaluation of dual DNA-PK and PI-3K inhibitors.
Author(s): Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson C, Cano C, Tavecchio M, Barbeau J, Bardos J, Cornell L, Griffin RJ, Menear KA, Slade A, Thommes P, Martin NMB, Newell DR, Smith GCM, Curtin NJ
Publication type: Article
Publication status: Published
Journal: Molecular Cancer Therapeutics
Year: 2012
Volume: 11
Issue: 8
Pages: 1789-1798
Print publication date: 01/08/2012
ISSN (print): 1535-7163
ISSN (electronic): 1538-8514
Publisher: American Association for Cancer Research
URL: http://dx.doi.org/10.1158/1535-7163.MCT-11-0535
DOI: 10.1158/1535-7163.MCT-11-0535
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