title: Combined gene expression profiling and RNAi screening in clear cell renal cell carcinoma identify PLK1 and other therapeutic kinase targets.
abstract: In recent years, several molecularly targeted therapies have been approved for clear cell renal cell carcinoma (ccRCC), a highly aggressive cancer. Although these therapies significantly extend overall survival, nearly all patients with advanced ccRCC eventually succumb to the disease. To identify other molecular targets, we profiled gene expression in 90 ccRCC patient specimens for which tumor grade information was available. Gene set enrichment analysis indicated that cell-cycle-related genes, in particular, Polo-like kinase 1 (PLK1), were associated with disease aggressiveness. We also carried out RNAi screening to identify kinases and phosphatases that when inhibited could prevent cell proliferation. As expected, RNAi-mediated knockdown of PLK1 and other cell-cycle kinases was sufficient to suppress ccRCC cell proliferation. The association of PLK1 in both disease aggression and in vitro growth prompted us to examine the effects of a small-molecule inhibitor of PLK1, BI 2536, in ccRCC cell lines. BI 2536 inhibited the proliferation of ccRCC cell lines at concentrations required to inhibit PLK1 kinase activity, and sustained inhibition of PLK1 by BI 2536 led to dramatic regression of ccRCC xenograft tumors in vivo. Taken together, these findings highlight PLK1 as a rational therapeutic target for ccRCC.
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Zhang
authors.forename: Josh
authors.initials: J
authors.lastname: Smith
authors.forename: David
authors.initials: D
authors.lastname: Petillo
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Looyenga
authors.forename: Kristin
authors.initials: K
authors.lastname: Feenstra
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Mackeigan
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Furge
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011621:Pteridines / Q000494:pharmacology / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1; C518477:BI 2536