| Summary: | <p>Abstract</p> <p>Background</p> <p>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).</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>Motesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC<sub>50 </sub>= 18 nM) and exon 11 (V560 D, IC<sub>50 </sub>= 5 nM; Δ552-559, IC<sub>50 </sub>= 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC<sub>50 </sub>= 77 nM; V560D/T670I, IC<sub>50 </sub>= 277 nM; Y823 D, IC<sub>50 </sub>= 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC<sub>50 </sub>> 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC<sub>50 </sub>values in good agreement with those observed in the autophosphorylation assays.</p> <p>Conclusions</p> <p>In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.</p>
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