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.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Carcinoma, Renal Cell / drug therapy
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Carcinoma, Renal Cell / enzymology*
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / pathology
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / physiology
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Cell Line, Tumor / drug effects
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Female
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Gene Expression Profiling*
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Humans
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Kidney Neoplasms / drug therapy
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Kidney Neoplasms / enzymology*
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Kidney Neoplasms / genetics
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Kidney Neoplasms / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Molecular Targeted Therapy*
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Neoplasm Invasiveness / genetics
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / physiology
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Polo-Like Kinase 1
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / physiology
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Pteridines / pharmacology
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Pteridines / therapeutic use*
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RNA Interference*
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RNA, Small Interfering / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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BI 2536
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Cell Cycle Proteins
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pteridines
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RNA, Small Interfering
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Protein Serine-Threonine Kinases