Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (part 1)

Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for, and underlying mechanisms of, KrasG12D–independent PDAC recurrence. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquired amplification and overexpression of the transcriptional co-activator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D–independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC. To evaluate the potential for recurrence mechanisms following KrasG12D extinction in p48Cre tetO_LKrasG12D ROSA_rtTAL+ p53L+ mice, we utilized MRI imaging to monitor regression of advanced pancreatic tumors measuring at least 8 mm in diameter at time of doxycycline withdrawal. Primary relapsed pancreatic tumor lines were established from eight independent tumors. These lines (E1-E16) were cultured in the absence of doxycycline for 24 hours and total cellular RNA was prepared. For control samples, two iKras lines (described in Ying et al., 2012) were cultured in the presence of doxycycline and total cellular RNA was prepared.