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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4355-4364. Prepublished online as a Blood First Edition Paper on February 11, 2008; DOI 10.1182/blood-2007-09-113175. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-09-113175v1 111/8/4355    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gontarewicz, A. Articles by Brümmendorf, T. H. Search for Related Content PubMed PubMed Citation Articles by Gontarewicz, A. Articles by Brümmendorf, T. H. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I Artur Gontarewicz1, Stefan Balabanov1, Gunhild Keller1, Riccardo Colombo2, Alessio Graziano2, Enrico Pesenti2, Daniel Benten3, Carsten Bokemeyer1, Walter Fiedler1, Jürgen Moll2, and Tim H. Brümmendorf1 1 Klinik für Onkologie und Hämatologie, Universitäres Cancer Center, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; 2 Nerviano Medical Sciences Oncology, Milan, Italy; and 3 Klinik für Gastroenterologie, Zentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against a broad panel of human BCR-ABL–positive and –negative cell lines and against murine BaF3 cells ectopically expressing wild-type (wt) or IM-resistant BCR-ABL mutants, including T315I. Pharmacologic synergism of IM and PHA-739358 was observed in leukemia cell lines with subtotal resistance to IM. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3, a marker of Aurora B activity and of CrkL, a downstream target of Bcr-Abl, suggesting that PHA-739358 acts via combined inhibition of Bcr-Abl and Aurora kinases. Moreover, strong antiproliferative effects of PHA-739358 were observed in CD34+ cells derived from untreated CML patients and from IM-resistant individuals in chronic phase or blast crisis, including those harboring the T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM-resistant BCR-ABL-positive leukemias, including those harboring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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