Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors

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, IC(50 )= 18 nM) and exon 11 (V560 D, IC(50 )= 5 nM; Δ552-559, IC(50 )= 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC(50 )= 77 nM; V560D/T670I, IC(50 )= 277 nM; Y823 D, IC(50 )= 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC(50 )> 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC(50 )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.