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Departments of Medical Oncology [A. F., Z-Z. P., M. v. M., A. K. G.] and Surgical Oncology [S. C., J. P. A., B. E.], and Bioinformatics, Department of Information Science and Technology [M. O.], Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111; Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [J. F.]; and Graduate Program in the Department of Molecular Biology and Biotechnology, Russian State Medical University, 117869 Moscow, Russia [A. F., O. F.]

² To whom requests for reprints should be addressed, at Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111. Phone: (215) 728-2205; Fax: (215) 728-2741; E-mail: A_Godwin{at}fccc.edu

Gastrointestinal stromal tumors (GISTs), defined by the presence of constitutively activated KIT, are the most common gastrointestinal mesenchymal malignancies. This observation has been successfully exploited in clinical trials of Gleevec (also known as imatinib mesylate, STI-571) for patients with unresectable and/or metastatic GISTs. The biological mechanisms of Gleevec as well as its downstream molecular effects are generally unknown. We used a DNA microarray-based approach to identify gene expression patterns and signaling pathways that were altered in response to Gleevec in GIST cells. We identified a total of 148 genes or expressed sequence tags (of 10,367) that were differentially regulated; 7 known genes displayed a durable response after treatment. The significantly down-regulated genes were SPRY4A, FZD8, PDE2A, RTP801, FLJ20898, and ARHGEF2. The only up-regulated gene was MAFbx. On a functional level, we demonstrated that imatinib inhibited phosphorylation of KIT, AKT, and extracellular signal-regulated kinase 1/2 without affecting the total level of these proteins and that differential expression of these response genes involved activation of mitogen-activated protein kinase-dependent and -independent pathways. In an attempt to correlate these in vitro findings to clinical data, we examined GIST needle biopsy specimens taken from patients before and after Gleevec administration according to the CSTI571-B2222 Phase II trial and demonstrated that expression levels of the two gene transcripts evaluated correlated well with clinical response. This study emphasizes the potential value of an in vitro cell model to investigate GIST response to imatinib in vivo, for the purpose of identifying important genetic markers of clinical response, mechanisms of drug action, and possible therapeutic targets.