Functional annotation of rare gene aberration drivers of pancreatic cancer.

TitleFunctional annotation of rare gene aberration drivers of pancreatic cancer.
Publication TypeJournal Article
Year of Publication2016
AuthorsTsang, YHuen, Dogruluk, T, Tedeschi, PM, Wardwell-Ozgo, J, Lu, H, Espitia, M, Nair, N, Minelli, R, Chong, Z, Chen, F, Chang, QEdward, Dennison, JB, Dogruluk, A, Li, M, Ying, H, Bertino, JR, Gingras, M-C, Ittmann, M, Kerrigan, J, Chen, K, Creighton, CJ, Eterovic, K, Mills, GB, Scott, KL
JournalNat Commun
Volume7
Pagination10500
Date Published2016 Jan 25
ISSN2041-1723
KeywordsAnimals, Carcinogenesis, Cell Line, Tumor, Female, Humans, Mice, Mice, Nude, Mutation, Pancreatic Neoplasms, Phosphotransferases (Alcohol Group Acceptor), Reactive Oxygen Species
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.

DOI10.1038/ncomms10500
Alternate JournalNat Commun
PubMed ID26806015
PubMed Central IDPMC4737758
Grant ListU01 CA168394 / CA / NCI NIH HHS / United States
P30CA125123 / CA / NCI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
R01CA138701 / CA / NCI NIH HHS / United States
U01CA168394 / CA / NCI NIH HHS / United States
R01 CA138701 / CA / NCI NIH HHS / United States