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

Weisberg, Ellen, Kung, Andrew L., Wright, Renee D., Moreno, Daisy, Catley, Laurie, Ray, Arghya, Zawel, Leigh, Tran, Mary, Cools, Jan, Gilliland, Gary, Mitsiades, Constantine, McMillin, Douglas W., Jiang, Jingrui, Hall-Meyers, Elizabeth and Griffin, James D. (2007) Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells. Molecular Cancer Therapeutics, 6 7: 1951-1961. doi:10.1158/1535-7163.MCT-06-0810


Author Weisberg, Ellen
Kung, Andrew L.
Wright, Renee D.
Moreno, Daisy
Catley, Laurie
Ray, Arghya
Zawel, Leigh
Tran, Mary
Cools, Jan
Gilliland, Gary
Mitsiades, Constantine
McMillin, Douglas W.
Jiang, Jingrui
Hall-Meyers, Elizabeth
Griffin, James D.
Title Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells
Journal name Molecular Cancer Therapeutics   Check publisher's open access policy
ISSN 1535-7163
Publication date 2007-07
Year available 2007
Sub-type Article (original research)
DOI 10.1158/1535-7163.MCT-06-0810
Volume 6
Issue 7
Start page 1951
End page 1961
Total pages 11
Language eng
Formatted 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.
Keyword Internal Tandem Duplication
Acute Myeloid-Leukemia
Tyrosine Kinase
Activating Mutation
Survivin Expression
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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