title: Kinomic exploration of temozolomide and radiation resistance in Glioblastoma multiforme xenolines.
abstract: OBJECTIVE
  Glioblastoma multiforme (GBM) represents the most common and deadly primary brain malignancy, particularly due to temozolomide (TMZ) and radiation (RT) resistance. To better understand resistance mechanisms, we examined global kinase activity (kinomic profiling) in both treatment sensitive and resistant human GBM patient-derived xenografts (PDX or "xenolines").
  
  
  METHODS
  Thirteen orthotopically-implanted xenolines were examined including 8 with known RT sensitivity/resistance, while 5 TMZ resistant xenolines were generated through serial TMZ treatment in vivo. Tumors were harvested, prepared as total protein lysates, and kinomically analyzed on a PamStation®12 high-throughput microarray platform with subsequent upstream kinase prediction and network modeling.
  
  
  RESULTS
  Kinomic profiles indicated elevated tyrosine kinase activity associated with the radiation resistance phenotype, including FAK and FGFR1. Furthermore, network modeling showed VEGFR1/2 and c-Raf hubs could be involved. Analysis of acquired TMZ resistance revealed more kinomic variability among TMZ resistant tumors. Two of the five tumors displayed significantly altered kinase activity in the TMZ resistant xenolines and network modeling indicated PKC, JAK1, PI3K, CDK2, and VEGFR as potential mediators of this resistance.
  
  
  CONCLUSIONS
  GBM xenolines provide a phenotypic model for GBM drug response and resistance that when paired with kinomic profiling identified targetable pathways to inherent (radiation) or acquired (TMZ) resistance.
authors.affiliation: The University of Alabama at Birmingham, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Anderson
authors.affiliation: Maine Medical Center Research Institute, Portland, USA.
authors.forename: Christine W
authors.initials: CW
authors.lastname: Duarte
authors.affiliation: The University of Alabama at Birmingham, USA; University of Alexandria, Egypt.
authors.forename: Karim
authors.initials: K
authors.lastname: Welaya
authors.affiliation: The University of Alabama at Birmingham, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Rohrbach
authors.affiliation: The University of Alabama at Birmingham, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Bredel
authors.affiliation: The University of Alabama at Birmingham, USA.
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
authors.affiliation: The University of Alabama at Birmingham, USA.
authors.forename: Nirmal V
authors.initials: NV
authors.lastname: Choradia
authors.affiliation: Southern Research Institute, Birmingham, USA.
authors.forename: Jaideep V
authors.initials: JV
authors.lastname: Thottassery
authors.affiliation: The University of Alabama at Birmingham, USA.
authors.forename: George
authors.initials: G
authors.lastname: Yancey Gillespie
authors.affiliation: The University of Alabama at Birmingham, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Bonner
authors.affiliation: The University of Alabama at Birmingham, USA. Electronic address: cwilley@uab.edu.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Willey
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011836:Radiation Tolerance; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D011505:Protein-Tyrosine Kinases; D000077204:Temozolomide
keywords: Array profiling; Glioblastoma; Kinomics; Temozolomide; Xenolines