Functional annotation of rare gene aberration drivers of pancreatic cancer

Nat Commun. 2016 Jan 25;7:10500. doi: 10.1038/ncomms10500.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinogenesis
  • Cell Line, Tumor
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Mutation
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Phosphotransferases (Alcohol Group Acceptor)
  • NAD kinase

Supplementary concepts

  • Pancreatic Carcinoma