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Blood, 1 January 2006, Vol. 107, No. 1, pp. 293-300. Prepublished online as a Blood First Edition Paper on September 8, 2005; DOI 10.1182/blood-2005-06-2469. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-06-2469v1 107/1/293    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Heidel, F. Articles by Fischer, T. Search for Related Content PubMed PubMed Citation Articles by Heidel, F. Articles by Fischer, T. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain Florian Heidel, Fian K. Solem, Frank Breitenbuecher, Daniel B. Lipka, Stefan Kasper, M. H. Thiede, Christian Brandts, Hubert Serve, Johannes Roesel, Francis Giles, Eric Feldman, Gerhard Ehninger, Gary J. Schiller, Stephen Nimer, Richard M. Stone, Yanfeng Wang, Thomas Kindler, Pamela S. Cohen, Christoph Huber, and Thomas Fischer From the Johannes-Gutenberg University, 3rd Medical Department, Mainz; Thanares Analytik und Research, Dresden; University of Münster, Medical Department A, Münster; University Carl Gustav Carus, 1st Medical Department, Dresden, Germany; Novartis Pharma, Basel, Switzerland; M. D. Anderson Cancer Center, Houston, TX; Cornell University Cancer Center, New York, NY; UCLA Medical Center, Los Angeles, CA; Memorial Sloan Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; and Novartis Oncology, Florham Park, NJ. Activating mutations in the FLT3 tyrosine kinase (TK) occur in approximately 35% of patients with acute myeloid leukemia (AML). Therefore, targeting mutated FLT3 is an attractive therapeutic strategy, and early clinical trials testing FLT3 TK inhibitors (TKI) showed measurable clinical responses. Most of these responses were transient; however, in a subset of patients blast recurrence was preceded by an interval of prolonged remission. The etiology of clinical resistance to FLT3-TKI in AML is unclear but is of major significance for the development of future therapeutic strategies. We searched for mechanisms of resistance in 6 patients with AML who had relapses upon PKC412 treatment. In an index AML patient, an algorithm of analyses was applied using clinical material. In vivo and in vitro investigation of primary blasts at relapse revealed persistent TK phosphorylation of FLT3 despite sufficient PKC412 serum levels. Through additional molecular analyses, we identified a single amino acid substitution at position 676 (N676K) within the FLT3 kinase domain as the sole cause of resistance to PKC412 in this patient. Reconstitution experiments expressing the N676K mutant in 32D cells demonstrated that FLT3-ITD-N676K was sufficient to confer an intermediate level of resistance to PKC412 in vitro. These studies point out that a genetically complex malignancy such as AML may retain dependence on a single oncogenic signal. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. W. Lane, D. T. Scadden, and D. G. 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