title: High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes.
abstract: Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM's and MAPKAPK's in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Anderson
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Willey
authors.affiliation: Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Amitkumar
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Clinical Oncology Department, University of Alexandria, Alexandria, Egypt.
authors.forename: Karim
authors.initials: K
authors.lastname: Welaya
authors.affiliation: Division of Preventative Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Dongquan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Center for Outcomes Research and Evaluation (CORE), Maine Medical Center Research Institute (MMCRI), Portland, Maine, United States of America.
authors.forename: Christine W
authors.initials: CW
authors.lastname: Duarte
authors.affiliation: Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Pooja
authors.initials: P
authors.lastname: Ghatalia
authors.affiliation: Clinical Oncology Department, University of Alexandria, Alexandria, Egypt.
authors.forename: Waleed
authors.initials: W
authors.lastname: Arafat
authors.affiliation: Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Ankit
authors.initials: A
authors.lastname: Madan
authors.affiliation: Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sudarshan
authors.affiliation: Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Gurudatta
authors.initials: G
authors.lastname: Naik
authors.affiliation: Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.affiliation: Department of Medical Oncology, Kidney Cancer Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D011494:Protein Kinases