Abstract
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.
Highlights
DNA lesions resulting in activation of the ataxia telangiectasiamutated (ATM) and ATM-Rad3-related (ATR) protein kinases in response to double-strand DNA breaks (DSBs) and replication stress, respectively.[7,8,9]
VE-822 did not inhibit ATM, Chk[2] or DNA-PK phosphorylation in response to radiation, which further supports the selectivity of VE-822 for ATR (Supplementary Figure S1)
We investigated the potential of VE-822, a potent ATR inhibitor (ATRi), to sensitize pancreatic ductal adenocarcinoma (PDAC) cells and xenografts to XRT and gemcitabine
Summary
DNA lesions resulting in activation of the ataxia telangiectasiamutated (ATM) and ATM-Rad3-related (ATR) protein kinases in response to double-strand DNA breaks (DSBs) and replication stress, respectively.[7,8,9] Defects in the DNA damage response (DDR) such as ATM and p53 deletion/ mutation are common in human tumors[10] and occur in up to 70% of patients with PDAC.[1,11,12,13] They might lead to a differential response in DNA repair signaling between normal and tumor cells that could be exploited to increase killing of cancer cells with DNA-damaging agents without increasing normal cell toxicity.[7,14] Defects in one component of the DDR may result in tumor cells relying on the remaining intact DDR pathways, such as ATR, for survival upon DNA damage.[15,16,17,18,19,20,21,22].
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