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**ATR inhibitor + gemcitabine** is a combination therapy where an ATR (axia telangiectasia and Rad3-related) kinase inhibitor is paired with gemcitabine, a nucleoside analog chemotherapy that induces DNA damage by inhibiting DNA synthesis and causing replication stress. ATR inhibitors block the DNA damage response pathway, preventing repair of gemcitabine-induced lesions, leading to synergistic cell killing through excessive replication fork collapse, unscheduled origin firing, and apoptosis, particularly in pancreatic ductal adenocarcinoma (PDAC) cells and platinum-resistant ovarian cancers. This pairing has shown broad synergy across PDAC cell lines and patient-derived organoids, with clinical trials evaluating safety and efficacy in advanced solid tumors.[1][3][5][7]
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