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Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors.

AbstractBACKGROUND:
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.
AuthorsSean Caenepeel, Lisa Renshaw-Gegg, Angelo Baher, Tammy L Bush, Will Baron, Todd Juan, Raffi Manoukian, Andrew S Tasker, Anthony Polverino, Paul E Hughes
JournalJournal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 29 Pg. 96 (Jul 15 2010) ISSN: 1756-9966 [Electronic] England
PMID20633291 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Indoles
  • Oligonucleotides
  • Niacinamide
  • Proto-Oncogene Proteins c-kit
  • imetelstat
Topics
  • Animals
  • Blotting, Western
  • CHO Cells
  • Cell Proliferation
  • Cricetinae
  • Cricetulus
  • Female
  • Gastrointestinal Stromal Tumors (drug therapy, genetics, pathology)
  • Humans
  • Indoles (pharmacology)
  • Mice
  • Mice, Inbred C57BL
  • Mutation (genetics)
  • Niacinamide (analogs & derivatives, pharmacology)
  • Oligonucleotides
  • Phosphorylation
  • Proto-Oncogene Proteins c-kit (antagonists & inhibitors, genetics)

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