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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.

One of the major goals for the post-genome era is determining of the function of proteins predicted in the genome sequence. In many organisms functional assignments have been the results of comparative sequencing, proteomics or expression profiling. In the yeast, Saccharomyces cerevisiae, however, the functional role of a gene can be tested directly by disrupting the gene and examining the phenotype of the mutant. Because precise targeted deletions can be easily constructed, it is also possible to systematically delete every gene in the genome. Here we describe recent progress in yeast genome-wide mutagenesis programs and the results produced from analyzing the mutants created by them.