title: Outlier kinase expression by RNA sequencing as targets for precision therapy.
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.
authors: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors: Vishal
authors: V
authors: Kothari
authors: Iris
authors: I
authors: Wei
authors: Sunita
authors: S
authors: Shankar
authors: Shanker
authors: S
authors: Kalyana-Sundaram
authors: Lidong
authors: L
authors: Wang
authors: Linda W
authors: LW
authors: Ma
authors: Pankaj
authors: P
authors: Vats
authors: Catherine S
authors: CS
authors: Grasso
authors: Dan R
authors: DR
authors: Robinson
authors: Yi-Mi
authors: YM
authors: Wu
authors: Xuhong
authors: X
authors: Cao
authors: Diane M
authors: DM
authors: Simeone
authors: Arul M
authors: AM
authors: Chinnaiyan
authors: Chandan
authors: C
authors: Kumar-Sinha
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling / Q000379:methods; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000096:biosynthesis / Q000235:genetics; D017423:Sequence Analysis, RNA / Q000379:methods*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D051499:Receptor, Fibroblast Growth Factor, Type 4; D018631:ras Proteins; C117307:KRAS protein, human; C496371:FGFR4 protein, human
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