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Research Articles

Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells

¹ Dana-Farber Cancer Institute and ² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, and ³ Brigham and Women's Hospital, Boston, Massachusetts; ⁴ Novartis Institutes of Biomedical Research, Cambridge, Massachusetts; ⁵ Mater Health Services, Brisbane, Australia; and ⁶ Department of Molecular and Developmental Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, Belgium

Requests for reprints: James D. Griffin, Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-3360; Fax: 617-632-4388. E-mail: James_Griffin{at}dfci.harvard.edu

Abstract

Members of the inhibitor of apoptosis protein (IAP) family play a role in mediating apoptosis. Studies suggest that these proteins may be a viable target in leukemia because they have been found to be variably expressed in acute leukemias and are associated with chemosensitivity, chemoresistance, disease progression, remission, and patient survival. Another promising therapeutic target, FLT3, is mutated in about one third of acute myelogenous leukemia (AML) patients; promising results have recently been achieved in clinical trials investigating the effects of the protein tyrosine kinase inhibitor PKC412 on AML patients harboring mutations in the FLT3 protein. Of growing concern, however, is the development of drug resistance resulting from the emergence of point mutations in targeted tyrosine kinases used for treatment of acute leukemia patients. One approach to overriding resistance is to combine structurally unrelated inhibitors and/or inhibitors of different signaling pathways. The proapoptotic IAP inhibitor, LBW242, was shown in proliferation studies done in vitro to enhance the killing of PKC412-sensitive and PKC412-resistant cell lines expressing mutant FLT3 when combined with either PKC412 or standard cytotoxic agents (doxorubicin and Ara-c). In addition, in an in vivo imaging assay using bioluminescence as a measure of tumor burden, a total of 12 male NCr-nude mice were treated for 10 days with p.o. administration of vehicle, LBW242 (50 mg/kg/day), PKC412 (40 mg/kg/day), or a combination of LBW242 and PKC412; the lowest tumor burden was observed in the drug combination group. Finally, the combination of LBW242 and PKC412 was sufficient to override stromal-mediated viability signaling conferring resistance to PKC412. [Mol Cancer Ther 2007;6(7):1951–61]

Grant support: J.D. Griffin is supported by NIH grant CA66996 and a Specialized Center of Research Award from the Leukemia and Lymphoma Society. J.D. Griffin is also supported by NIH grants CA36167 and DK50654. L. Zawel and M. Tran are employees of Novartis Pharma AG, Basel, Switzerland. J.D. Griffin has a financial interest with Novartis Pharma AG.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: E. Weisberg and A.L. Kung contributed equally to this work.

⁷ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 12/31/06; revised 3/28/07; accepted 5/15/07.