Kinome-wide siRNA screening identifies molecular targets mediating the sensitivity of pancreatic cancer cells to Aurora kinase inhibitors

Biochem Pharmacol. 2012 Feb 15;83(4):452-61. doi: 10.1016/j.bcp.2011.11.005. Epub 2011 Nov 15.

Abstract

Aurora kinases are a family of mitotic kinases that play important roles in the tumorigenesis of a variety of cancers including pancreatic cancer. A number of Aurora kinase inhibitors (AKIs) are currently being tested in preclinical and clinical settings as anti-cancer therapies. However, the antitumor activity of AKIs in clinical trials has been modest. In order to improve the antitumor activity of AKIs in pancreatic cancer, we utilized a kinome focused RNAi screen to identify genes that, when silenced, would sensitize pancreatic cancer cells to AKI treatment. A total of 17 kinase genes were identified and confirmed as positive hits. One of the hits was the platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), which has been shown to be overexpressed in pancreatic cancer cells and tumor tissues. Imatinib, a PDGFR inhibitor, significantly enhanced the anti-proliferative effect of ZM447439, an Aurora B specific inhibitor, and PHA-739358, a pan-Aurora kinase inhibitor. Further studies showed that imatinib augmented the induction of G2/M cell cycle arrest and apoptosis by PHA-739358. These findings indicate that PDGFRA is a potential mediator of AKI sensitivity in pancreatic cancer cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Aurora Kinase B
  • Aurora Kinases
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism*
  • Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Receptor, Platelet-Derived Growth Factor alpha
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases