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Originally published as JCO Early Release 10.1200/JCO.2006.06.2265 on September 5 2006

Journal of Clinical Oncology, Vol 24, No 29 (October 10), 2006: pp. 4764-4774
© 2006 American Society of Clinical Oncology.
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Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors

Michael C. Heinrich, Christopher L. Corless, Charles D. Blanke, George D. Demetri, Heikki Joensuu, Peter J. Roberts, Burton L. Eisenberg, Margaret von Mehren, Christopher D.M. Fletcher, Katrin Sandau, Karen McDougall, Wen-bin Ou, Chang-Jie Chen, Jonathan A. Fletcher

From the Division of Hematology/Oncology, Department of Pathology, Oregon Health & Science University Cancer Institute, Oregon Health & Science University; Portland Veterans Affairs Medical Center, Portland, OR; Dana-Farber Cancer Institute; Harvard Cancer Center; Department of Pathology, Brigham & Women's Hospital, Boston, MA; Division of Oncologic Surgery, Hitchcock-Dartmouth Medical Center, Lebanon, NH; Division of Medical Oncology, Fox-Chase Cancer Center, Philadelphia, PA; Novartis Pharmaceuticals Corporation, Hanover, NJ; University of Helsinki, Helsinki; and the Department of Surgery, University of Turku, Turku, Finland

Address reprint requests to Michael C. Heinrich, MD, R&D-19 3710 U.S. Veterans Hospital Rd, Portland, OR 97239; e-mail: Heinrich{at}ohsu.edu

PURPOSE: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem.

PATIENTS AND METHODS: One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity.

RESULTS: Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways.

CONCLUSION: Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.

published online ahead of print at www.jco.org on September 5, 2006.

Supported in part by Novartis Pharmaceuticals, VA Merit Review Grant (M.C.H.), GIST Cancer Research Fund (M.C.H.), B.P., Lester and Regina John Foundation (M.C.H.).

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


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