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Blood, 1 May 2007, Vol. 109, No. 9, pp. 4006-4015. Prepublished online as a Blood First Edition Paper on January 11, 2007; DOI 10.1182/blood-2006-09-045039. This Article Full Text (PDF) All Versions of this Article: blood-2006-09-045039v1 109/9/4006    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 Nguyen, T. K. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Nguyen, T. K. Articles by Grant, S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 5, 2006 Accepted November 15, 2006 MEK1/2 inhibitors sensitize BCR/ABL+ human leukemia cells to the dual ABL/SRC inhibitor BMS354825 Tri K. Nguyen, Mohamed Rahmani, Hisashi Harada, Paul Dent, and Steven Grant* Department of Medicine, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA Department of Biochemistry, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA Department of Pharmacology, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA * Corresponding author; email: stgrant{at}hsc.vcu.edu. Interactions between MEK1/2 inhibitors and the dual Abl/Src kinase inhibitor dasatinib (BMS-354825) were examined in chronic myeloid leukemia (CML) cell lines and primary specimens. Co-treatment of K562 or LAMA cells with subtoxic or marginally toxic concentrations of PD184352 (or U0126) and dasatinib synergistically potentiated mitochondrial damage, caspase activation, and apoptosis. Similar interactions were observed in CD34+ cells from one CML patient-derived but not in a normal human CD34+ bone marrow cell specimen. These interactions were associated with multiple perturbations in survival signaling pathways, including inactivation of Bcr/Abl, STAT5, ERK1/2, down-regulation of Bcl-xL, Mcl-1, and dephosphorylation/activation of Bim. They were also associated with BAX/BAK conformational change, mitochondrial dysfunction, and caspase activation. Bim knockdown by shRNA suppressed BAX and BAK conformational change and protected cells from dasatinib/PD184352 lethality. Conversely, K562 cells ectopically expressing Mcl-1 or Bcl-xL were significantly less susceptible to dasatinib/PD184352 toxicity. Notably, the dasatinib/PD184352 regimen was active against leukemic cells exhibiting various forms of imatinib mesylate resistance, including Bcr/Abl overexpression, Lyn activation, and several Bcr/Abl kinase domain mutations (e.g., E255K, M351T), but not T315I. Together, these findings suggest that strategies combining dasatanib with MEK1/2 inhibitors warrants further investigation in Bcr/Abl+ malignancies, particularly in the setting of imatinib mesylate-resistant disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Comparison of imatinib mesylate, 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 Blood 2006 108: 2332-2338. 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