Abstract
Protein kinases represent the most effective class of therapeutic targets in cancer; therefore, determination of kinase aberrations is a major focus of cancer genomic studies. Here, we analyzed transcriptome sequencing data from a compendium of 482 cancer and benign samples from 25 different tissue types, and defined distinct "outlier kinases" in individual breast and pancreatic cancer samples, based on highest levels of absolute and differential expression. Frequent outlier kinases in breast cancer included therapeutic targets like ERBB2 and FGFR4, distinct from MET, AKT2, and PLK2 in pancreatic cancer. Outlier kinases imparted sample-specific dependencies in various cell lines, as tested by siRNA knockdown and/or pharmacologic inhibition. Outlier expression of polo-like kinases was observed in a subset of KRAS-dependent pancreatic cancer cell lines, and conferred increased sensitivity to the pan-PLK inhibitor BI-6727. Our results suggest that outlier kinases represent effective precision therapeutic targets that are readily identifiable through RNA sequencing of tumors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Line, Tumor
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Gene Expression Profiling / methods
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Gene Knockdown Techniques
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Humans
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Male
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Molecular Targeted Therapy
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Neoplasms / drug therapy*
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Neoplasms / enzymology*
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Neoplasms / genetics
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / enzymology
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Pancreatic Neoplasms / genetics
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Protein Kinases / biosynthesis*
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Protein Kinases / genetics
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins p21(ras)
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RNA Interference
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Random Allocation
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Receptor, ErbB-2 / biosynthesis
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Receptor, ErbB-2 / genetics
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Receptor, Fibroblast Growth Factor, Type 4 / biosynthesis
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Receptor, Fibroblast Growth Factor, Type 4 / genetics
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Sequence Analysis, RNA / methods*
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Xenograft Model Antitumor Assays
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ras Proteins / biosynthesis
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ras Proteins / genetics
Substances
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KRAS protein, human
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Protein Kinases
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FGFR4 protein, human
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Receptor, ErbB-2
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Receptor, Fibroblast Growth Factor, Type 4
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Proto-Oncogene Proteins p21(ras)
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ras Proteins