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Resistance to c-KIT kinase inhibitors conferred by V654A mutation


Roberts, KG and Odell, AF and Byrnes, EM and Baleato, RM and Griffith, R and Lyons, AB and Ashman, LK, Resistance to c-KIT kinase inhibitors conferred by V654A mutation, Molecular Cancer Therapeutics, 6, (3) pp. 1159-1166. ISSN 1535-7163 (2007) [Refereed Article]

DOI: doi:10.1158/1535-7163.MCT-06-0641


Certain mutations within c-KIT cause constitutive activation of the receptor and have been associated with several human malignancies. These include gastrointestinal stromal tumors (GIST), mastocytosis, acute myelogenous leukemia, and germ cell tumors. The kinase inhibitor imatinib potently inhibits c-KIT and is approved for treatment of GIST. However, secondary point mutations can develop within the kinase domain to confer resistance to imatinib and cause drug-resistant relapse. A common mutation, which results in a V654A substitution, has been documented in imatinib-resistant GIST patients. We expressed c-KIT cDNA constructs encoding the V654A substitution alone and in combination with a typical activating exon 11 mutation characteristic of GIST, V560G, in factor-dependent FDC-P1 cells. The V654A substitution alone resulted in enhanced proliferation in c-KIT ligand (stem cell factor) but not factor independence. Cells expressing the double mutant were, like those expressing single V560G mutant c-KIT, factor independent. Analysis of cellular proliferation in the presence of imatinib showed that the V654A substitution alone conferred resistance. The difference in sensitivity was especially pronounced for cells expressing single mutant V560G c-KIT compared with double mutant V560G/V654A c-KIT. The findings were supported by studies of c-KIT phosphorylation. Analysis of the crystal structure of imatinib in complex with the kinase domain of c-KIT predicts that the V654A substitution directly affects the binding of imatinib to the receptor. Alternative c-KIT inhibitors, nilotinib (AMN107) and PKC412, were also less active on V560G/V654A c-KIT than on the V560G single mutant; however, nilotinib, like imatinib, potently inhibited the V560G mutant. PKC412 strongly inhibited imatinib-resistant D816V c-KIT

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Oncology and carcinogenesis
Research Field:Molecular targets
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Lyons, AB (Associate Professor Bruce Lyons)
ID Code:73625
Year Published:2007
Web of Science® Times Cited:68
Deposited By:Medicine
Deposited On:2011-10-19
Last Modified:2011-10-19

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