Stepwise epigenetic reorganization occurs during reprogramming of somatic cells into induced pluripotent stem cells. The faithful shutdown of the somatic program occurs in the early stage of reprogramming. Taking advantage of such properties of cellular reprogramming, we examined the effect of in vivo reprogramming on Kras-induced cancer development. We show that the transient expression of reprogramming factors in pancreatic acinar cells results in the transient repression of acinar cell enhancers, which are similarly observed in pancreatitis. We next demonstrate that Kras and p53 mutations are insufficient to induce ERK signaling in the pancreas. Notably, the transient expression of reprogramming factors in Kras mutant mice is sufficient to induce pancreatic ductal adenocarcinoma. In contrast, the forced expression of acinar cell-related transcription factors inhibits the pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells. These results underscore a crucial role of dedifferentiation-associated epigenetic regulations in the initiation of pancreatic cancers. We propose that iPS cell technology could be a powerful tool to study the impact of epigenetic regulation in disease pathogenesis.