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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1652-1659. Prepublished online as a Blood First Edition Paper on September 30, 2004; DOI 10.1182/blood-2004-06-2445. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-06-2445v1 105/4/1652    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 von Bubnoff, N. Articles by Duyster, J. Search for Related Content PubMed PubMed Citation Articles by von Bubnoff, N. Articles by Duyster, J. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies the mutation pattern for PD166326, an alternative Abl kinase inhibitor Nikolas von Bubnoff, Darren R. Veach, Heiko van der Kuip, Walter E. Aulitzky, Jana Sänger, Petra Seipel, William G. Bornmann, Christian Peschel, Bayard Clarkson, and Justus Duyster From the Department of Internal Medicine III, Technical University of Munich, Munich, Germany; Memorial Sloan-Kettering Cancer Center, New York, NY; Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; and the Department of Internal Medicine II, Robert Bosch Hospital, Stuttgart, Germany. In Philadelphia-positive (Ph+) leukemia, point mutations within the Bcr-Abl kinase domain emerged as a major mechanism of resistance to imatinib mesylate. We established a cell-based screening strategy for detection of clinically relevant point mutations using Bcr-Abl-transformed Ba/F3 cells. We identified 32 different single-point mutations within the kinase domain of Bcr-Abl. The pattern and frequency of mutations in this cell culture-based screen resembled the pattern and frequency observed in resistant patients. We then applied this screen to an alternative Abl kinase inhibitor. Using PD166326, the frequency of resistant colonies emerging at 5 to 10 times the median growth inhibition (IC50) of PD166326 was significantly lower than with imatinib. In addition, PD166326 produced a distinct pattern of Bcr-Abl mutations. The majority of mutations that came up with both imatinib and PD166326 could effectively be suppressed by increasing the dose of PD166326 to 50 to 500 nM. In contrast, only a few mutations could be suppressed by increasing the imatinib dose to 5 to 10 µM. However, 3 mutations affecting F317 displayed complete resistance to PD166326, but could be effectively inhibited by standard concentrations of imatinib. Thus, this robust and simple screening system provides a rational basis for combinatorial and sequential treatment strategies in targeted cancer therapy. (Blood. 2005;105: 1652-1659) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. O'Hare, C. A. Eide, J. W. Tyner, A. S. Corbin, M. J. Wong, S. Buchanan, K. Holme, K. A. Jessen, C. Tang, H. A. Lewis, et al. SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib PNAS, April 8, 2008; 105(14): 5507 - 5512. [Abstract] [Full Text] [PDF] A. Ray, S. W. Cowan-Jacob, P. W. Manley, J. Mestan, and J. D. 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