Abstract
Abstract 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. We utilized MRI imaging to monitor regression of advanced pancreatic tumors measuring at least 8 mm in diameter at time of doxycycline withdrawal. Here we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression, downstream canonical MAPK signaling but instead acquired amplification and overexpression of the transcriptional co-activator Yap1. Enforced Yap1 expression can substitute for oncogenic Kras-driven tumor maintenance and associated tumor cell proliferation without activation of canonical Kras signaling surrogates. 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 indicates that the oncogenic Kras-independent relapse tumors generated in response to KrasG12D extinction closely resemble the quasimesenchymal-subtype of human PDAC and rely on alternative oncogenic mechanisms including Yap1 for their growth. Citation Format: Avnish Kapoor, Wantong Yao, Haoqiang Ying, Sujun Hua, Alison Liewen, Anguraj Sadanandam, Ramsey Al-Khalil, Andrea Viale, Piergiorgio Pettazzoni, Nora Sanchez, Alexei Protopopov, Jianhua Zhang, Timothy Heffernan, Randy L. Johnson, Lynda Chin, Y. Alan Wang, Giulio Draetta, Ronald A. DePinho. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A94.
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