@article{ab6b48dbbe1948bdb22c23f2c44851e3,
title = "Yap1 activation enables bypass of oncogenic KRAS addiction in pancreatic cancer",
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 the 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 acquire amplification and overexpression of the transcriptional coactivator 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.",
author = "Avnish Kapoor and Wantong Yao and Haoqiang Ying and Sujun Hua and Alison Liewen and Qiuyun Wang and Yi Zhong and Wu, {Chang Jiun} and Anguraj Sadanandam and Baoli Hu and Qing Chang and Chu, {Gerald C.} and Ramsey Al-Khalil and Shan Jiang and Hongai Xia and Eliot Fletcher-Sananikone and Carol Lim and Horwitz, {Gillian I.} and Andrea Viale and Piergiorgio Pettazzoni and Nora Sanchez and Huamin Wang and Alexei Protopopov and Jianhua Zhang and Timothy Heffernan and Johnson, {Randy L.} and Lynda Chin and Wang, {Y. Alan} and Giulio Draetta and Depinho, {Ronald A.}",
note = "Funding Information: We thank the laboratory of Kun-Liang Guan, William Kaelin, Jiandie D. Lin, Hiroshi Sasaki, and Marius Sudol for sharing various reagents; Mien-Chie Hung and William Hahn for sharing unpublished data; Douglas Hanahan for helpful suggestions and support for PDAC subtype analysis; Shreya Malu for help with the graphical abstract; and Giannicola Genovese, Sharmistha Sarkar, Shruti Malu, Simona Colla, and other members of the DePinho laboratory for helpful suggestions and technical support. We would also like to thank the Small Animal Imaging Facility, Flow Cytometry and Cellular Imaging Core, Histopathology Core, Sequencing and Non-Coding RNA Core Services at The University of Texas, MD Anderson Cancer Center (Cancer Center Support grant, CA16672). Funding Information: The project was supported by 5U01CA084313 (R.A.D.), P01CA117969 (R.A.D.), R56DK094865 (R.L.J.) from National Institutes of Health; UT Star Award (R.A.D.); American-Italian Cancer Foundation Award (G.D.); NHS funding to the National Institute for Health Research (NIHR) Biomedical Research Centre for Cancer (A.S.); and Discovery Award W81XWH-12-1-0459 from Department of Defense (H.Y.). G.D., H.Y., and T.H. were also supported by funds from the Sheikh Ahmed Center for Pancreatic Cancer Research at the University of Texas MD Anderson Cancer Center. Additional support was provided by the Jane Coffin Childs Postdoctoral Fellowship to A.K. (61-1512), Damon Runyon Foundation Postdoctoral Fellowship to S.H., and TRIUMPH Postdoctoral Fellowship to N.S. ",
year = "2014",
month = jul,
day = "3",
doi = "10.1016/j.cell.2014.06.003",
language = "English (US)",
volume = "158",
pages = "185--197",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",
}