Here, we used a Kras+/G12D TP53+/R172H Pdx1-Cre–derived (KPC-derived) model of pancreatic adenocarcinoma to examine the tumor response and adaptive resistance mechanisms involved in response to 2 established methods of hypoxia-reducing therapy: the hypoxia-activated prodrug TH-302 and vascular endothelial growth factor receptor 2 (VEGFR-2) blockade. Here, TP53 is linked to pancreatic adenocarcinoma.