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Ref Type Journal Article
PMID (20633291)
Authors Caenepeel S, Renshaw-Gegg L, Baher A, Bush TL, Baron W, Juan T, Manoukian R, Tasker AS, Polverino A, Hughes PE
Title Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors.
Journal Journal of experimental & clinical cancer research : CR
Vol 29
Issue
Date 2010 Jul 15
URL
Abstract Text 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).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.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.In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
KIT M552_V559del deletion gain of function - predicted KIT M552_V559del results in the deletion of eight amino acids in the juxtamembrane domain (exon 11) of the Kit protein from amino acids 552 to 559 (PMID: 20633291). K550_K558del results in constitutive Kit phosphorylation in cell culture in one study (PMID: 20633291) and therefore, is predicted to lead to a gain of Kit protein function.
KIT V560D missense gain of function KIT V560D lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 19164557). V560D confers a gain of function on Kit, as indicated by constitutive phosphorylation of Kit in cell culture (PMID: 16954519, PMID: 20633291).
KIT Y823D missense gain of function KIT Y823D lies within the protein kinase domain of the Kit protein (UniProt.org). Y823D confers a gain of function on Kit, as indicated by constitutive phosphorylation of Kit in cultured cells (PMID: 14695343, PMID: 20633291).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT V560D KIT V654A Advanced Solid Tumor sensitive Motesanib Diphosphate Preclinical - Cell culture Actionable In a preclinical study, Motesanib (AMG 706) inhibited KIT phosphorylation and growth of cells expressing a KIT V560D/V654A double mutation in culture (PMID: 20633291). 20633291
KIT V560D Advanced Solid Tumor sensitive Motesanib Diphosphate Preclinical - Cell culture Actionable In a preclinical study, Motesanib (AMG 706) inhibited KIT phosphorylation and growth of cells expressing KIT V560D in culture (PMID: 20633291). 20633291
KIT V560D KIT T670I Advanced Solid Tumor sensitive Motesanib Diphosphate Preclinical - Cell culture Actionable In a preclinical study, Motesanib (AMG 706) inhibited KIT phosphorylation and growth of cells expressing a KIT V560D/T670I double mutation in culture (PMID: 20633291). 20633291
KIT M552_V559del Advanced Solid Tumor sensitive Motesanib Diphosphate Preclinical - Cell culture Actionable In a preclinical study, Motesanib (AMG 706) inhibited KIT phosphorylation and growth of cells expressing KIT M552_V559del in culture (PMID: 20633291). 20633291
KIT Y823D Advanced Solid Tumor sensitive Motesanib Diphosphate Preclinical - Cell culture Actionable In a preclinical study, Motesanib (AMG 706) inhibited KIT phosphorylation and growth of cells expressing KIT Y823D in culture (PMID: 20633291). 20633291