Pancreatic cancer is a notoriously deadly disease with a five-year survival rate around 10 percent. Since early detection of these tumors is difficult, pancreatic cancers are often diagnosed at advanced stages. At this point, genotoxic chemotherapeutics can be used to manage tumor growth. However, side effects of these drugs are severe, limiting the amount of treatment that can be given and resulting in sub-optimal dosing. Thus, there is an urgent need to identify chemo-sensitizing agents that can lower the effective dose of genotoxic agents and as a result reduce the side effects. Here, we use transformed and non-transformed pancreatic cell lines to evaluate DNA repair inhibitors as chemo-sensitizing agents. We used a novel next generation sequencing approach to demonstrate that pancreatic cancer cells have a reduced ability to faithfully repair DNA damage. We then determine the extent that two DNA repair inhibitors (CCS1477, a small molecule inhibitor of p300, and ART558, a small molecule inhibitor of polymerase theta) can exploit this repair deficiency to make pancreatic cancer cells more sensitive to cisplatin, a commonly used genotoxic chemotherapeutic. Immunofluorescence microscopy and cell viability assays show that CCS1477 delayed repair and significantly sensitized pancreatic cancer cells to cisplatin. The increased toxicity was not seen in a non-transformed pancreatic cell line. We also found that while ART558 sensitizes pancreatic cancer cells to cisplatin, it also sensitized non-transformed pancreatic cancer cells.
Keywords: Alternative end joining; DNA repair; P300; Pancreatic cancer; Synthetic lethality.
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