@article{0bce55ea03494570a9d69704138622fe,
title = "Functional annotation of rare gene aberration drivers of pancreatic cancer",
abstract = "As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC). This approach reveals oncogenic activity for rare gene aberrations in genes including NAD Kinase (NADK), which regulates NADP(H) homeostasis and cellular redox state. We further validate mutant NADK, whose expression provides gain-of-function enzymatic activity leading to a reduction in cellular reactive oxygen species and tumorigenesis, and show that depletion of wild-type NADK in PDAC cell lines attenuates cancer cell growth in vitro and in vivo. These data indicate that annotating rare aberrations can reveal important cancer signalling pathways representing additional therapeutic targets.",
author = "Tsang, {Yiu Huen} and Turgut Dogruluk and Tedeschi, {Philip M.} and Joanna Wardwell-Ozgo and Hengyu Lu and Maribel Espitia and Nikitha Nair and Rosalba Minelli and Zechen Chong and Fengju Chen and Chang, {Qing Edward} and Dennison, {Jennifer B.} and Armel Dogruluk and Min Li and Haoqiang Ying and Bertino, {Joseph R.} and Gingras, {Marie Claude} and Michael Ittmann and John Kerrigan and Ken Chen and Creighton, {Chad J.} and Karina Eterovic and Mills, {Gordon B.} and Scott, {Kenneth L.}",
note = "Funding Information: We thank Kristen Karlin and Trey Westbrook for providing and consulting on use of the pINDUCER vector system23 used to express KRASG12D. This project was supported in part by the Genomic and RNA Profiling Core at Baylor College of Medicine with funding from the NIH/NCI grant (P30CA125123). This work was supported by the Cancer Prevention and Research Institute of Texas (CPRIT; RP120046), Lustgarten Foundation (RFP-B-042) and the 2014 Pancreatic Cancer Action Network—AACR Career Development Award (14-20-25-SCOT) by funding to K.L.S. This work was also supported by the NIH (UO1CA168394) by funding to K.L.S and G.B.M. T.D. was supported by a training grant from The Cullen Foundation. H.L. was supported by a training grant from CPRIT (RP140102). J.B.D. was supported by the American Cancer Society Joe and Jessie Crump Postdoctoral Fellowship. M.L. was supported by the NIH (R01CA138701). Publisher Copyright: {\textcopyright} 2016, Nature Publishing Group. All rights reserved.",
year = "2016",
month = jan,
day = "25",
doi = "10.1038/ncomms10500",
language = "English (US)",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}