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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 (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 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 Gontarewicz, A. Articles by Brummendorf, T. H. Search for Related Content PubMed PubMed Citation Articles by Gontarewicz, A. Articles by Brummendorf, T. H. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 17, 2007 Accepted January 27, 2008 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 Gontarewicz, Stefan Balabanov, Gunhild Keller, Riccardo Colombo, Alessio Graziano, Enrico Pesenti, Daniel Benten, Carsten Bokemeyer, Walter Fiedler, Jurgen Moll, and Tim H. Brummendorf* Klinik fur Onkologie und Hamatologie, Universitares Cancer Center (UCCH), Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany Nerviano Medical Sciences S.r.l.-Oncology, Milan, Italy Klinik fur Gastroenterologie, Zentrum fur Innere Medizin, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany * Corresponding author; email: t.bruemmendorf{at}uke.uni-hamburg.de. 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 the novel small molecule inhibitor, PHA-739358 which selectively targets Bcr-Abl and Aurora kinases A-C. PHA-739358 exhibits strong antiproliferative and pro-apoptotic 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. Pharmacological synergism of IM and PHA-739358 was observed in leukemia cell lines with sub-total resistance to IM. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3, a marker of Aurora B activity and of CrkL, a down-stream 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 harbouring the T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM resistant BCR-ABL positive leukemias, including those harbouring 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? This article has been cited by other articles: R. B. Cohen, S. F. Jones, C. Aggarwal, M. von Mehren, J. Cheng, D. R. Spigel, F. A. Greco, M. Mariani, M. Rocchetti, R. Ceruti, et al. A Phase I Dose-Escalation Study of Danusertib (PHA-739358) Administered as a 24-Hour Infusion with and without Granulocyte Colony-Stimulating Factor in a 14-Day Cycle in Patients with Advanced Solid Tumors Clin. Cancer Res., November 1, 2009; 15(21): 6694 - 6701. [Abstract] [Full Text] [PDF] N. Steeghs, F. A.L.M. Eskens, H. Gelderblom, J. Verweij, J. W.R. Nortier, J. Ouwerkerk, C. van Noort, M. Mariani, R. Spinelli, P. Carpinelli, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor Danusertib in Patients With Advanced or Metastatic Solid Tumors J. Clin. Oncol., October 20, 2009; 27(30): 5094 - 5101. [Abstract] [Full Text] [PDF] D. S. Boss, J. H. Beijnen, and J. H.M. Schellens Clinical Experience with Aurora Kinase Inhibitors: A Review Oncologist, August 1, 2009; 14(8): 780 - 793. [Abstract] [Full Text] [PDF] J. Cortes When Imatinib Fails, What Else Is There? ASCO Educational Book, January 1, 2009; 2009(1): 402 - 406. [Abstract] [Full Text] [PDF] L.-Y. Lu, J. L. Wood, L. Ye, K. Minter-Dykhouse, T. L. Saunders, X. Yu, and J. Chen Aurora A Is Essential for Early Embryonic Development and Tumor Suppression J. Biol. Chem., November 14, 2008; 283(46): 31785 - 31790. [Abstract] [Full Text] [PDF] J. V. Melo and C. Chuah Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond Hematology, January 1, 2008; 2008(1): 427 - 435. [Abstract] [Full Text] [PDF]

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