Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation

Antonescu, C. R., Besmer, P., Guo, T., Arkun, K., Hom, G., Koryotowski, B., Leversha, M. A., Jeffrey, P. D., Desantis, D., Singer, S., Brennan, M. F., Maki, R. G., DeMatteo, R. P. (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res, 11 (11). pp. 4182-90. ISSN 1078-0432 (Print)1078-0432 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/15930355
DOI: 10.1158/1078-0432.CCR-04-2245

Abstract

Most gastrointestinal stromal tumors (GIST) have an activating mutation in either KIT or PDGFRA. Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST. It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy. To identify the mechanism of resistance, we studied 31 patients with GIST who were treated with imatinib and then underwent surgical resection. There were 13 patients who were nonresistant to imatinib, 3 with primary resistance, and 15 with acquired resistance after initial benefit from the drug. There were no secondary mutations in KIT or PDGFRA in the nonresistant or primary resistance groups. In contrast, secondary mutations were found in 7 of 15 (46%) patients with acquired resistance, each of whom had a primary mutation in KIT exon 11. Most secondary mutations were located in KIT exon 17. KIT phosphorylation was heterogeneous and did not correlate with clinical response to imatinib or mutation status. That acquired resistance to imatinib in GIST commonly occurs via secondary gene mutation in the KIT kinase domain has implications for strategies to delay or prevent imatinib resistance and to employ newer targeted therapies.

Item Type: Paper
Uncontrolled Keywords: Adult Aged Aged, 80 and over Amino Acid Sequence Antineoplastic Agents/pharmacology/therapeutic use Benzamides Blotting, Western DNA Mutational Analysis Drug Resistance, Neoplasm/drug effects/*genetics Female Gastrointestinal Stromal Tumors/*drug therapy/genetics/pathology Genotype Humans Imatinib Mesylate Male Middle Aged Molecular Sequence Data *Mutation Piperazines/pharmacology/*therapeutic use Protein-Tyrosine Kinases/antagonists & inhibitors Proto-Oncogene Proteins c-kit/genetics/metabolism Pyrimidines/pharmacology/*therapeutic use Receptor, Platelet-Derived Growth Factor alpha/genetics/metabolism
Subjects: 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 Deposited: 26 Oct 2016 20:16
Last Modified: 26 Oct 2016 20:16
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33656

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