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Clinical Cancer Research Vol. 11, 4182-4190, June 1, 2005
© 2005 American Association for Cancer Research

Cancer Therapy: Preclinical

Acquired Resistance to Imatinib in Gastrointestinal Stromal Tumor Occurs Through Secondary Gene Mutation

Cristina R. Antonescu1, Peter Besmer4, Tianhua Guo1, Knarik Arkun1, Glory Hom1, Beata Koryotowski1, Margaret A. Leversha5, Philip D. Jeffrey6, Diann Desantis2, Samuel Singer2, Murray F. Brennan2, Robert G. Maki3 and Ronald P. DeMatteo2

Authors' Affiliations: Departments of 1 Pathology, 2 Surgery, and 3 Medicine, 4 Memorial Sloan-Kettering Cancer Center and Developmental Biology, 5 Cell Biology, and 6 Structural Biology and Programs, Sloan-Kettering Institute, New York, New York

Requests for reprints: Cristina R. Antonescu, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-5721; Fax: 212-717-3203; E-mail: antonesc{at}mskcc.org..

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.

Key Words: gastrointestinal stromal tumor • KIT • PDGFRA • receptor tyrosine kinase • imatinib • resistance




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