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Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2002-05-1361. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-05-1361v1 100/8/3041    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gorre, M. E. Articles by Sawyers, C. L. Search for Related Content PubMed PubMed Citation Articles by Gorre, M. E. Articles by Sawyers, C. L. Related Collections Neoplasia Oncogenes and Tumor Suppressors Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 October 2002, Vol. 100, No. 8, pp. 3041-3044 BRIEF REPORT BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90 Mercedes E. Gorre, Katharine Ellwood-Yen, Gabriela Chiosis, Neal Rosen, and Charles L. Sawyers From the Department of Medicine and Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, CA; the Department of Medicine and Program in Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY. Clinical resistance to imatinib mesylate is commonly observed in patients with advanced Philadelphia chromosome- positive (Ph+) leukemias. Acquired resistance is typically associated with reactivation of BCR-ABL due to kinase domain mutations or gene amplification, indicating that BCR-ABL remains a viable target for inhibition in these patients. Strategies for overcoming resistance can be envisioned through exploitation of other molecular features of the BCR-ABL protein, such as its dependence on the molecular chaperone heat shock protein 90 (Hsp90). To determine whether inhibition of Hsp90 could induce degradation of imatinib mesylate-resistant, mutant BCR-ABL proteins, hematopoietic cells expressing 2 mutant BCR-ABL proteins found in imatinib mesylate-resistant patients (T315I and E255K) were examined for sensitivity to geldanamycin and 17-allylaminogeldanamycin (17-AAG). Both compounds induced the degradation of wild-type and mutant BCR-ABL and inhibited cell growth, with a trend indicating more potent activity against mutant BCR-ABL proteins. These data support clinical investigations of 17-AAG in imatinib mesylate-resistant Ph+ leukemias. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T.-S. Lee, W. Ma, X. Zhang, F. Giles, J. Cortes, H. Kantarjian, and M. Albitar BCR-ABL alternative splicing as a common mechanism for imatinib resistance: evidence from molecular dynamics simulations Mol. Cancer Ther., December 1, 2008; 7(12): 3834 - 3841. [Abstract] [Full Text] [PDF] T. P. Hughes, S. Branford, D. L. White, J. Reynolds, R. Koelmeyer, J. F. Seymour, K. Taylor, C. Arthur, A. Schwarer, J. Morton, et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy Blood, November 15, 2008; 112(10): 3965 - 3973. [Abstract] [Full Text] [PDF] M. Kurokawa, C. Zhao, T. Reya, and S. 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