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Cancer Therapy: Clinical |
Authors' Affiliations: Departments of 1 Pathology, 2 Neuropathology, 3 Internal Medicine, and 4 Surgery, University of Bonn Medical School, Bonn, Germany; 5 Department of Internal Medicine, Hematology, and Oncology, Robert Roessle Hospital and Tumor Institute, Max Delbrueck Center for Molecular Medicine, Berlin-Buch, Germany; and 6 Department of Surgery, Division of Surgical Oncology and Thoracic Surgery, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Heidelberg, Germany
Requests for reprints: Eva Wardelmann, Department of Pathology, University of Bonn Medical School, P.O. Box 2120, D-53011 Bonn, Germany. Phone: 49-228-287-5353; Fax: 49-228-287-5030; E-mail: eva.wardelmann{at}ukb.uni-bonn.de.
Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor 
(PDGFR) gene. Both PDGFR and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.
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