Figure 3.

Pancreatic tumor development and maintenance by KRAS-dependent and KRAS-independent mechanisms via YAP activation. Oncogenic KRAS mutation is a key event of the development of PanIN lesions. Acinar-to-ductal metaplasia (ADM) caused by pancreatitis is an initiating step in pancreatic tumor development. The pancreatic tumor mouse model LSL-KRAS^G12D; Pdx1-Cre displays increased ADM lesions and development of PanIN in response to cerulein, accompanied by YAP/TAZ expression. On the other hand, deletion of YAP/TAZ reduces the ability of KRAS^G12D mutant mice to develop ADM in response to cerulein, and these mice are free of PanIN lesions even after cerulein-induced pancreatitis. Inactivation of KRAS^G12D in established tumor lesions can lead to tumor regression. Although KRAS^G12D extinction induces regression of pancreatic tumors, 70% of the mice develop relapsed tumors via oncogenic KRAS-independent mechanisms involving the YAP1 oncogene. An anti-YAP1 therapeutic strategy with KRAS-targeting agents may be required for elective tumors.