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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1328-1333. Prepublished online as a Blood First Edition Paper on April 13, 2006; DOI 10.1182/blood-2005-12-010132. This Article Full Text (PDF) All Versions of this Article: blood-2005-12-010132v1 108/4/1328    most recent Alert me when this article is cited Alert me if a correction is posted 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 16, 2005 Accepted March 30, 2006 Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107) Nikolas von Bubnoff*, Paul W Manley, Jurgen Mestan, Jana Sanger, Christian Peschel, and Justus Duyster Department of Internal Medicine III, Technical University of Munich, Munich, Germany Novartis Institutes of Biomedical Research, Basel, Switzerland * Corresponding author; email: n.bubnoff{at}lrz.tum.de. In advanced-phase CML, resistance to imatinib mesylate is associated with point mutations in the Bcr-Abl kinase domain. A new generation of potent Abl kinase inhibitors is undergoing clinical evaluation. It is important to generate specific resistance profiles for each of these compounds, which could translate into combinatorial and sequential treatment strategies. Having characterized nilotinib (AMN107) against a large panel of imatinib- resistant Bcr-Abl mutants, we investigated which mutants might arise under nilotinib therapy using a cell based resistance screen. In contrast to imatinib mesylate, resistance to nilotinib was associated with a limited spectrum of Bcr-Abl kinase mutations. Among these were mutations affecting the P-loop and T315I. Rarely emerging resistant colonies at a concentration of 400 nM nilotinib exclusively expressed the T315I mutation. With the exception of T315I, all of the mutations that were identified were effectively suppressed when the nilotinib concentration was increased to 2000 nM, which falls within the peak - trough range in plasma levels (3.6 - 1.7 µM) measured in patients treated with 400 mg bid. Our findings suggest that nilotinib might be superior to imatinib in terms of the development of resistance. However, our study indicates that clinical resistance to nilotinib may be associated with the predominant emergence of T315I. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. D. Press, S. G. Willis, J. Laudadio, M. J. Mauro, and M. W. N. Deininger Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib Blood, September 24, 2009; 114(13): 2598 - 2605. [Abstract] [Full Text] [PDF] E. Jabbour, D. Jones, H. M. Kantarjian, S. O'Brien, C. Tam, C. Koller, J. A. Burger, G. Borthakur, W. G. Wierda, and J. Cortes Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations Blood, September 3, 2009; 114(10): 2037 - 2043. [Abstract] [Full Text] [PDF] S. Soverini, A. Gnani, S. 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