title: Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors.
abstract: BACKGROUND
  Activating mutations in Kit receptor tyrosine kinase or the related platelet-derived growth factor receptor (PDGFR) play an important role in the pathogenesis of gastrointestinal stromal tumors (GIST).
  
  
  METHODS
  This study investigated the activity of motesanib, an inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; PDGFR; and Kit, against primary activating Kit mutants and mutants associated with secondary resistance to imatinib. Single- and double-mutant isoforms of Kit were evaluated for their sensitivity to motesanib or imatinib in autophosphorylation assays and in Ba/F3 cell proliferation assays.
  
  
  RESULTS
  Motesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC50 = 18 nM) and exon 11 (V560 D, IC50 = 5 nM; Delta552-559, IC50 = 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC50 = 77 nM; V560D/T670I, IC50 = 277 nM; Y823 D, IC50 = 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC50 > 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC50 values in good agreement with those observed in the autophosphorylation assays.
  
  
  CONCLUSIONS
  In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.
authors.affiliation: Department of Oncology Research, Amgen Inc,, One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Caenepeel
authors.forename: Lisa
authors.initials: L
authors.lastname: Renshaw-Gegg
authors.forename: Angelo
authors.initials: A
authors.lastname: Baher
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Bush
authors.forename: Will
authors.initials: W
authors.lastname: Baron
authors.forename: Todd
authors.initials: T
authors.lastname: Juan
authors.forename: Raffi
authors.initials: R
authors.lastname: Manoukian
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
authors.forename: Anthony
authors.initials: A
authors.lastname: Polverino
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hughes
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009841:Oligonucleotides; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D019009:Proto-Oncogene Proteins c-kit; C519562:imetelstat