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Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.

Original publication

DOI

10.1038/cddis.2012.181

Type

Journal article

Journal

Cell Death Dis

Publication Date

06/12/2012

Volume

3

Keywords

Animals, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Survival, Checkpoint Kinase 1, DNA Damage, Female, Humans, Isoxazoles, Mice, Mice, Inbred BALB C, Pancreatic Neoplasms, Phosphorylation, Protein Kinase Inhibitors, Protein Kinases, Protein-Serine-Threonine Kinases, Pyrazines, Radiation Tolerance, Radiation-Sensitizing Agents