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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3723-3734. Prepublished online as a Blood First Edition Paper on January 9, 2008; DOI 10.1182/blood-2007-09-114454. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2007-09-114454v1 111/7/3723    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 Weisberg, E. Articles by Griffin, J. D. Search for Related Content PubMed PubMed Citation Articles by Weisberg, E. Articles by Griffin, J. D. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL– and mutant FLT3-expressing cells Ellen Weisberg1, Lolita Banerji2, Renee D. Wright3, Rosemary Barrett1, Arghya Ray1, Daisy Moreno4, Laurence Catley5, Jingrui Jiang1, Elizabeth Hall-Meyers4, Maira Sauveur-Michel6, Richard Stone1,7, Ilene Galinsky1, Edward Fox8, Andrew L. Kung3, and James D. Griffin1 1 Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA; 2 PAREXEL International, Waltham, MA; 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA; 4 Animal Resources Facility, Dana-Farber Cancer Institute, Boston, MA; 5 Mater Health Services, South Brisbane, Australia; 6 Novartis Pharma, Basel, Switzerland; 7 Department of Medicine, Harvard Medical School, Department of Medicine, Brigham and Women's Hospital, Boston, MA; and 8 Molecular Diagnostics Laboratory, Dana-Farber Cancer Institute, Boston, MA Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhi-bitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL–, and induce apoptosis of BCR-ABL–expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL– and mutant FLT3-expressing cells both in vitro and in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. von Bubnoff, R. A. Engh, E. Aberg, J. Sanger, C. Peschel, and J. Duyster FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro Cancer Res., April 1, 2009; 69(7): 3032 - 3041. [Abstract] [Full Text] [PDF]

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