Abstract
Abstract Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and 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 majority tumors will undergo spontaneous regrowth following Kras oncogene extinction and, importantly, a subset of relapsed tumors remained devoid of KrasG12D expression and canonical MAPK signaling and acquired amplification and over-expression of Hippo effector, the Yap1 transcriptional co-activator. Functional studies established Yap1 and the Tead2 transcriptional factor in driving KrasG12D–independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to promote a cell cycle and DNA replication program and a quasimesenchymal phenotype with increased metastatic potential. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC. This abstract is also presented as Poster B21. Citation Format: Avnish Kapoor, Wantong Yao, Haoqiang Ying, Sujun Hua, Alison Liewen, Qiuyun Wang, Yi Zhong, Chang-Jiun Wu, Anguraj Sadanandam, Baoli Hu, Qing Chang, Gerald Chu, Ramsey Al-Khalil, Shan Jiang, Hongai Xia, Eliot Fletcher-Sananikone, Carol Lim, Gillian Horwitz, Andrea Viale, Piergiorgio Pettazzoni, Nora Sanchez, Huamin Wang, Alexei Protopopov, Jianhua Zhang, Timothy Heffernan, Randy Johnson, Lynda Chin, Alan Wang, Giulio Draetta, Ronald DePinho. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr PR01. doi: 10.1158/1557-3125.RASONC14-PR01
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