title: High chromosome number in hematological cancer cell lines is a negative predictor of response to the inhibition of Aurora B and C by GSK1070916.
abstract: BACKGROUND
  Aurora kinases play critical roles in mitosis and are being evaluated as therapeutic targets in cancer. GSK1070916 is a potent, selective, ATP competitive inhibitor of Aurora kinase B and C. Translation of predictive biomarkers to the clinic can benefit patients by identifying the tumors that are more likely to respond to therapies, especially novel inhibitors such as GSK1070916.
  
  
  METHODS
  59 Hematological cancer-derived cell lines were used as models for response where in vitro sensitivity to GSK1070916 was based on both time and degree of cell death. The response data was analyzed along with karyotype, transcriptomics and somatic mutation profiles to determine predictors of response.
  
  
  RESULTS
  20 cell lines were sensitive and 39 were resistant to treatment with GSK1070916. High chromosome number was more prevalent in resistant cell lines (p-value = 0.0098, Fisher Exact Test). Greater resistance was also found in cell lines harboring polyploid subpopulations (p-value = 0.00014, Unpaired t-test). A review of NOTCH1 mutations in T-ALL cell lines showed an association between NOTCH1 mutation status and chromosome number (p-value = 0.0066, Fisher Exact Test).
  
  
  CONCLUSIONS
  High chromosome number associated with resistance to the inhibition of Aurora B and C suggests cells with a mechanism to bypass the high ploidy checkpoint are resistant to GSK1070916. High chromosome number, a hallmark trait of many late stage hematological malignancies, varies in prevalence among hematological malignancy subtypes. The high frequency and relative ease of measurement make high chromosome number a viable negative predictive marker for GSK1070916.
authors.affiliation: GlaxoSmithKline Oncology Research, Cancer Metabolism, 1250 Collegeville Road, Collegeville, PA 19426, USA. christopher.moy@gsk.com
authors.forename: Christopher
authors.initials: C
authors.lastname: Moy
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Oleykowski
authors.forename: Ramona
authors.initials: R
authors.lastname: Plant
authors.forename: Joel
authors.initials: J
authors.lastname: Greshock
authors.forename: Junping
authors.initials: J
authors.lastname: Jing
authors.forename: Kurtis
authors.initials: K
authors.lastname: Bachman
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Hardwicke
authors.forename: Richard
authors.initials: R
authors.lastname: Wooster
authors.forename: Yan
authors.initials: Y
authors.lastname: Degenhardt
mesh_terms: D064107:Aurora Kinase B; D064127:Aurora Kinases; D001372:Aza Compounds / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000235:genetics*; D004171:Diploidy; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011123:Polyploidy; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics
chemical_list: D001372:Aza Compounds; C544308:GSK 1070916; D007211:Indoles; D051880:Receptors, Notch; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases