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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.
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Submitted September 24, 2007
Accepted December 13, 2007
Potentiation of anti-leukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells
Ellen Weisberg, Lolita Banerji, Renee D Wright, Rosemary Barrett, Arghya Ray, Daisy Moreno, Laurence Catley, Jingrui Jiang, Elizabeth Hall-Meyers, Maira Sauveur-Michel, Richard Stone, Ilene Galinsky, Edward Fox, Andrew L Kung, and James D Griffin*
Department of Medical Oncology/Hematologic Neoplasia, Dana Farber Cancer Institute, Boston, MA, United States
Feasibility Manager, Parexel International, Waltham, MA, United States
Department of Pediatric Oncology, Dana Farber Cancer Institute and Children's Hospital, Boston, MA, United States
Animal Resources Facility, Dana Farber Cancer Institute, Boston, MA, United States
Consultant Haematologist, Mater Health Services, South Brisbane, Queensland, Australia
Lab Head, DD2, NIBR Oncology, Novartis Pharma AG, Basel, Switzerland
Department of Medicine, Harvard Medical School, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States
Director, Molecular Diagnostics Laboratory, Dana Farber Cancer Institute, Boston, MA, United States
* Corresponding author; email: james_griffin{at}dfci.harvard.edu.
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 inhibitors. 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 non-antagonistic fashion against BCR-ABL- and mutant FLT3-expressing cells both in vitro and in vivo.
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