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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2332-2338. Prepublished online as a Blood First Edition Paper on June 13, 2006; DOI 10.1182/blood-2006-02-004580. This Article Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2006-02-004580v1 108/7/2332    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bradeen, H. A. Articles by Deininger, M. W Search for Related Content PubMed PubMed Citation Articles by Bradeen, H. A. Articles by Deininger, M. W Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 24, 2006 Accepted May 5, 2006 Comparison of imatinib, dasatinib (BMS-354825), and nilotinib (AMN107) in an n-ethyl-n-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations Heather A. Bradeen, Christopher A. Eide, Thomas O'Hare, Kara J. Johnson, Stephanie G. Willis, Francis Y. Lee, Brian J. Druker, and Michael W Deininger* Oregon Health&Science University Bristol-Myers Squibb HHMI/Oregon Health & Science University Oregon Health and Science University * Corresponding author; email: deininge{at}ohsu.edu. BMS-354825 (dasatinib) and AMN107 (nilotinib) are potent alternate Abl inhibitors with activity against many imatinib resistant BCR-ABL kinase domain (KD) mutants, except T315I. We used N-ethyl-N-nitrosourea (ENU)-exposed Ba/F3-p210BCR-ABL cells to compare incidence and types of KD mutants emerging in the presence of imatinib, dasatinib and nilotinib, alone and in dual combinations. Although ENU is expected to induce mutations in multiple proteins, resistant clones were almost exclusively BCR-ABL KD mutant at relevant concentrations of nilotinib and dasatinib, consistent with a central role of KD mutations for resistance to these drugs. Twenty different mutations were identified with imatinib, 10 with nilotinib (including only one novel mutation, E292V), and 9 with dasatinib. At intermediate drug levels the spectrum narrowed to F317V and T315I for dasatinib and Y253H, E255V, and T315I for nilotinib. Thus, cross resistance is limited to T315I, which is also the only mutant isolated at drug concentrations equivalent to maximal achievable plasma trough levels. With drug combinations maximal suppression of resistant clone outgrowth was achieved at lower concentrations compared to single agents, suggesting that such combinations may be equipotent to higher dose single agents. However, sequencing uniformly revealed T315I, consistent with the need for a T315I inhibitor to completely block resistance. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825 Tri K. Nguyen, Mohamed Rahmani, Hisashi Harada, Paul Dent, and Steven Grant Blood 2007 109: 4006-4015. [Abstract] [Full Text] [PDF] Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias Ellen Weisberg, Laurie Catley, Renee D. Wright, Daisy Moreno, Lolita Banerji, Arghya Ray, Paul W. Manley, Juergen Mestan, Doriano Fabbro, Jingrui Jiang, Elizabeth Hall-Meyers, Linda Callahan, Jamie L. DellaGatta, Andrew L. Kung, and James D. Griffin Blood 2007 109: 2112-2120. [Abstract] [Full Text] [PDF]

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