Yap1 activation enables bypass of oncogenic KRAS addiction in pancreatic cancer

Activating mutations in KRASare among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras(G12D) driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1and the transcriptional factor Tead2in driving Kras(G12D)-independent tumor maintenance. The Yap1/ Tead2complex acts cooperatively with E2Ftranscription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidencefrom human PDAC models, portend a novel mechanism of escape from oncogenic Krasaddiction in PDAC.