Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance

Guo, T., Hajdu, M., Agaram, N. P., Shinoda, H., Veach, D., Clarkson, B. D., Maki, R. G., Singer, S., Dematteo, R. P., Besmer, P., Antonescu, C. R. (November 2009) Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance. Clin Cancer Res, 15 (22). pp. 6862-70. ISSN 1078-0432 (Print)1078-0432 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/19861442
DOI: 10.1158/1078-0432.CCR-09-1315

Abstract

PURPOSE: Although tyrosine kinase inhibitors have improved survival in advanced gastrointestinal stromal tumor (GIST), complete response is rare and most patients eventually fail the first-line treatment with imatinib. Sunitinib malate is the only approved second-line therapy for patients with imatinib-resistant or imatinib-intolerant GIST. The clinical benefit of sunitinib is genotype-dependent in regards to both primary and secondary mutations, with GIST patients harboring the KIT(AY502-3ins) exon 9 mutation being the most sensitive. EXPERIMENTAL DESIGN: As sunitinib resistance is now emerging, our goal was to investigate mechanisms of progression and to test the efficacy of novel tyrosine kinase inhibitor on these resistant mutants in vitro. N-ethyl-N-nitrosourea mutagenesis of Ba/F3 cells expressing the KIT(AY502-3ins) mutant was used to investigate novel patterns of resistant mutations evolving in the presence of sunitinib. RESULTS: Tumors from patients who developed sunitinib resistance after at least 1 year of radiographic response were analyzed, showing similar findings of a primary KIT(AY502-3ins) mutation and a secondary mutation in the KIT activation loop. Ba/F3 cells expressing these sunitinib-resistant double mutants showed sensitivity to both dasatinib and nilotinib. CONCLUSIONS: Sunitinib resistance in GIST shares similar pathogenetic mechanisms identified in imatinib failure, with acquisition of secondary mutations in the activation domain after an extended initial response to the drug. Moreover, in vitro mutagenesis with or without N-ethyl-N-nitrosourea of Ba/F3 cells expressing KIT(AY502-3ins) showed acquisition of secondary mutations restricted to the second kinase domain of KIT. In contrast, in vitro resistance to imatinib produces a broader spectrum of secondary mutations including mutations in both KIT kinase domains.

Item Type: Paper
Uncontrolled Keywords: Animals Antineoplastic Agents/pharmacology Apoptosis Cell Line Cell Proliferation *Drug Resistance, Neoplasm Exons Gastrointestinal Stromal Tumors/*drug therapy/*genetics Genotype Humans Indoles/*pharmacology Mice Mutagenesis *Mutation Proto-Oncogene Proteins c-kit/*genetics Pyrroles/*pharmacology
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons
diseases & disorders > cancer > cancer types > gastrointestinal stromal tumors
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations > mutagenesis
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 November 2009
Date Deposited: 25 Oct 2016 20:36
Last Modified: 25 Oct 2016 20:36
PMCID: PMC2783687
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33699

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