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Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 13(16)
- Publication Year :
- 2007
-
Abstract
- 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 (KITV654A, KITT670I, KITD820Y, and KITN822K) 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 KITWK557-8del/T670I, which was resistant to other kinase inhibitors. Although all three drugs tested decreased cell proliferation and inhibited KIT activation against exon 13 (KITV560del/V654A) and exon 17 (KITV559D/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 KITWK557-8del/T670I cells were sensitive only to sorafenib inhibition, whereas nilotinib was more potent on imatinib-resistant KITV560del/V654A and KITV559D/D820Y mutant cells than dasatinib and sorafenib.
- Subjects :
- Sorafenib
Niacinamide
Cancer Research
Stromal cell
Gastrointestinal Stromal Tumors
Pyridines
Dasatinib
Antineoplastic Agents
Apoptosis
Biology
Piperazines
Mice
medicine
Animals
Humans
Stromal tumor
Phosphorylation
Protein Kinase Inhibitors
Cell Proliferation
Phenylurea Compounds
Benzenesulfonates
Imatinib
Proto-Oncogene Proteins c-kit
Thiazoles
Imatinib mesylate
Pyrimidines
Oncology
Nilotinib
Drug Resistance, Neoplasm
Benzamides
Mutation
Cancer research
Imatinib Mesylate
Tyrosine kinase
medicine.drug
Subjects
Details
- ISSN :
- 10780432
- Volume :
- 13
- Issue :
- 16
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....9b68c4862e41906307176332cfbc2125