Blasco et al. show that ablation of Egfr and Raf1 results in complete regression of a subset of mutant Kras/Trp53-induced pancreatic ductal adenocarcinomas (PDAC) without overt toxicity. Inhibition of EGFR and c-RAF expression also blocks the progression of patient-derived PDAC xenografts with mutant KRAS/TP53.