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

Guo, T., Agaram, N. P., Wong, G. C., Hom, G., D'Adamo, D., Maki, R. G., Schwartz, G. K., Veach, D., Clarkson, B. D., Singer, S., DeMatteo, R. P., Besmer, P., Antonescu, C. R. (August 2007) Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor. Clin Cancer Res, 13 (16). pp. 4874-81. ISSN 1078-0432 (Print)1078-0432 (Linking)

DOI: 10.1158/1078-0432.CCR-07-0484


PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Item Type: Paper
Uncontrolled Keywords: Animals Antineoplastic Agents/*pharmacology Apoptosis/drug effects Benzamides Benzenesulfonates/*pharmacology Cell Proliferation/drug effects Dasatinib Drug Resistance, Neoplasm Gastrointestinal Stromal Tumors/*drug therapy/genetics Humans Imatinib Mesylate Mice *Mutation Niacinamide/analogs & derivatives Phenylurea Compounds Phosphorylation Piperazines/*pharmacology Protein Kinase Inhibitors/*pharmacology Proto-Oncogene Proteins c-kit/*genetics Pyridines/*pharmacology Pyrimidines/*pharmacology Thiazoles/pharmacology
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > gastrointestinal stromal tumors
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: 15 August 2007
Date Deposited: 26 Oct 2016 19:17
Last Modified: 26 Oct 2016 19:17
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