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Ref Type

Journal Article

PMID

(17699867)

Authors

Guo T, Agaram NP, Wong GC, Hom G, D'Adamo D, Maki RG, Schwartz GK, Veach D, Clarkson BD, Singer S, DeMatteo RP, Besmer P, Antonescu CR

Title

Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	13	16	2007 Aug 15	4874-81	Clin Cancer Res

URL

Abstract Text

Resistance is commonly acquired in patients with metastatic gastrointestinal stromal tumor who are treated with imatinib mesylate, often due to the development of secondary mutations in the KIT kinase domain. We sought to investigate the efficacy of second-line tyrosine kinase inhibitors, such as sorafenib, dasatinib, and nilotinib, against the commonly observed imatinib-resistant KIT mutations (KIT(V654A), KIT(T670I), KIT(D820Y), and KIT(N822K)) expressed in the Ba/F3 cellular system.In vitro drug screening of stable Ba/F3 KIT mutants recapitulating the genotype of imatinib-resistant patients harboring primary and secondary KIT mutations was investigated. Comparison was made to imatinib-sensitive Ba/F3 KIT mutant cells as well as Ba/F3 cells expressing only secondary KIT mutations. The efficacy of drug treatment was evaluated by proliferation and apoptosis assays, in addition to biochemical inhibition of KIT activation.Sorafenib was potent against all imatinib-resistant Ba/F3 KIT double mutants tested, including the gatekeeper secondary mutation KIT(WK557-8del/T670I), which was resistant to other kinase inhibitors. Although all three drugs tested decreased cell proliferation and inhibited KIT activation against exon 13 (KIT(V560del/V654A)) and exon 17 (KIT(V559D/D820Y)) double mutants, nilotinib did so at lower concentrations.Our results emphasize the need for tailored salvage therapy in imatinib-refractory gastrointestinal stromal tumors according to individual molecular mechanisms of resistance. The Ba/F3 KIT(WK557-8del/T670I) cells were sensitive only to sorafenib inhibition, whereas nilotinib was more potent on imatinib-resistant KIT(V560del/V654A) and KIT(V559D/D820Y) mutant cells than dasatinib and sorafenib.

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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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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
KIT	T670I	missense	gain of function	KIT T670I lies within the ATP pocket in the protein kinase domain of the Kit protein (PMID: 15236194, PMID: 22355224). T670I confers a gain of function on Kit as indicated by constitutive Kit phosphorylation, is transforming in cultured cells, and is associated with resistance to Kit inhibitors (PMID: 17699867, PMID: 15236194).	Y

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT V559D KIT D820Y	Advanced Solid Tumor	sensitive	Nilotinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tasigna (nilotinib) inhibited proliferation of transformed cells expressing a KIT V559D/D820Y double mutation in culture, with increased potency compared to Sprycel (dasatinib) or Nexavar (sorafenib) (PMID: 17699867).	17699867
KIT V559D KIT D820Y	Advanced Solid Tumor	sensitive	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) inhibited proliferation of transformed cells expressing a KIT V559D/D820Y double mutation in culture (PMID: 17699867).	17699867
KIT V559D KIT D820Y	Advanced Solid Tumor	sensitive	Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited proliferation of transformed cells expressing a KIT V559D/D820Y double mutation in culture (PMID: 17699867).	17699867
KIT V560del KIT V654A	Advanced Solid Tumor	sensitive	Nilotinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tasigna (nilotinib) inhibited proliferation of transformed cells expressing a KIT V560del/V654A double mutation in culture (PMID: 17699867).	17699867
KIT W557_K558del	Advanced Solid Tumor	sensitive	Nilotinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tasigna (nilotinib) inhibited growth of transformed cells expressing KIT W557_K558del in culture (PMID: 17699867).	17699867
KIT W557_K558del	Advanced Solid Tumor	sensitive	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) inhibited growth and induced apoptosis of transformed cells expressing KIT W557_K558del in culture (PMID: 17699867).	17699867
KIT W557_K558del KIT T670I	Advanced Solid Tumor	sensitive	Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited proliferation and induced apoptosis of transformed cells expressing a KIT W557_K558del/T670I double mutation in culture (PMID: 17699867).	17699867
KIT W557_K558del KIT T670I	Advanced Solid Tumor	resistant	Nilotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing a KIT W557_K558del/T670I double mutation demonstrated resistance to Tasigna (nilotinib) in culture (PMID: 17699867).	17699867
KIT W557_K558del KIT T670I	Advanced Solid Tumor	resistant	Dasatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing a KIT W557_K558del/T670I double mutation demonstrated resistance to Sprycel (dasatinib) in culture (PMID: 17699867).	17699867

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