title: 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.affiliation: Clinical Translational Research Division, Translational Genomic Research Institute (TGen), 13208 E Shea Blvd, Scottsdale, AZ 85259, USA.
authors.forename: Lifang
authors.initials: L
authors.lastname: Xie
authors.forename: Michelle
authors.initials: M
authors.lastname: Kassner
authors.forename: Ruben M
authors.initials: RM
authors.lastname: Munoz
authors.forename: Qiang Q
authors.initials: QQ
authors.lastname: Que
authors.forename: Jeff
authors.initials: J
authors.lastname: Kiefer
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Spyro
authors.initials: S
authors.lastname: Mousses
authors.forename: Hongwei H
authors.initials: HH
authors.lastname: Yin
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Haiyong
authors.initials: H
authors.lastname: Han
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D020796:Receptor, Platelet-Derived Growth Factor alpha; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases
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