GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Significance KRAS is mutated in more than 90% of pancreatic adenocarcinoma (PDAC). Despite its well-known role in cancer, development of drugs directly targeting KRAS has been unfruitful, underscoring the critical need to identify novel therapeutic targets. This study provides evidence that haploinsufficiency of a single cellular protein, GRP78, although having no harmful effect on the normal pancreas, is sufficient to impede Kras -driven pancreatic tumorigenesis in a genetically engineered mouse model. This study also establishes a role of GRP78 in acinar-to-ductal metaplasia, which is regarded as a precursor to PDAC development.