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

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.

• Authors: Lifang Xie, Michelle Kassner, Ruben M Munoz, Qiang Q Que, Jeff Kiefer, Yu Zhao, Spyro Mousses, Hongwei H Yin, Daniel D Von Hoff, Haiyong Han
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 83 Issue 4 Pg. 452-61 (Feb 15 2012) ISSN: 1873-2968 [Electronic] England
• PMID: 22100984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• Antineoplastic Agents (pharmacology, 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, enzymology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors)