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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	Vol	Issue	Date	Pages	Journal Short Title
Journal of experimental & clinical cancer research : CR	29		2010 Jul 15	96	J Exp Clin Cancer Res

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
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description
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: 16226710). M552_V559del results in constitutive Kit phosphorylation in cell culture (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 to Kit, as indicated by constitutive phosphorylation of Kit in cell culture (PMID: 16954519, PMID: 20633291, PMID: 27440273) despite reduced expression, enhanced degradation, and cellular mislocalization (PMID: 27440273).
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).

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 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 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

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