Functional annotation of rare gene aberration drivers of pancreatic cancer

Yiu Huen Tsang, Turgut Dogruluk, Philip M. Tedeschi, Joanna Wardwell-Ozgo, Hengyu Lu, Maribel Espitia, Nikitha Nair, Rosalba Minelli, Zechen Chong, Fengju Chen, Qing Edward Chang, Jennifer B. Dennison, Armel Dogruluk, Min Li, Haoqiang Ying, Joseph R. Bertino, Marie Claude Gingras, Michael Ittmann, John Kerrigan, Ken ChenChad J. Creighton, Karina Eterovic, Gordon Mills, Kenneth L. Scott

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Article number10500
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Jan 25 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Tsang, Y. H., Dogruluk, T., Tedeschi, P. M., Wardwell-Ozgo, J., Lu, H., Espitia, M., ... Scott, K. L. (2016). Functional annotation of rare gene aberration drivers of pancreatic cancer. Nature Communications, 7, [10500]. https://doi.org/10.1038/ncomms10500