FLT3 Expressing Leukemias Are Selectively Sensitive to Inhibitors of the Molecular Chaperone Heat Shock Protein 90 through Destabilization of Signal Transduction-Associated Kinases

• Published in: Clinical cancer research 2003-10, Vol.9 (12), p.4483-4493
• Main Authors: YAO, Qing, NISHIUCHI, Ritsuo, LI, Quanzhi, KUMAR, Ashish R, HUDSON, Wendy A, KERSEY, John H
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Apoptosis - drug effects; Benzoquinones; Biological and medical sciences; Cell Cycle - drug effects; Chemotherapy; Down-Regulation; Enzyme Inhibitors - pharmacology; Enzyme Stability - drug effects; fms-Like Tyrosine Kinase 3; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - chemistry; Humans; Intramolecular Oxidoreductases - metabolism; Lactams, Macrocyclic; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - enzymology; Leukemia, Myeloid - genetics; Medical sciences; Molecular Chaperones - antagonists & inhibitors; Molecular Chaperones - chemistry; Myeloid-Lymphoid Leukemia Protein; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Pharmacology. Drug treatments; Phosphorylation - drug effects; Polymerase Chain Reaction; Precipitin Tests; Prostaglandin-E Synthases; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-raf - metabolism; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Rifabutin - analogs & derivatives; Rifabutin - pharmacology; Signal Transduction - drug effects; Tumor Cells, Cultured
• ISSN: 1078-0432; 1557-3265

Purpose: We conducted studies to evaluate the hypothesis that FLT3 is a client of heat shock protein (Hsp) 90 and inhibitors of Hsp90 may be useful for therapy of leukemia. Experimental Design: The effects of the Hsp90-inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on cell growth, expression of signal transduction kinases, apoptosis, FLT3 phosphorylation and interaction with Hsp90 was determined in FLT3 + human leukemias. Results: We found that FLT3 is included in a multiprotein complex that includes Hsp90 and p23. 17-AAG inhibited FLT3 phosphorylation and interaction with Hsp90. FLT3 + leukemias were significantly more sensitive to the Hsp90 inhibitors 17-AAG and Herbimycin A in cell growth assays than FLT3-negative leukemias. Cells transfected with FLT3 became sensitive to 17-AAG. Cell cycle inhibition and apoptosis were induced by 17-AAG. Cells with constitutive expression of FLT3, as a result of internal tandem duplication, were the most sensitive; cells with wild-type FLT3 were intermediate in sensitivity, and FLT3-negative cells were the least sensitive. 17-AAG resulted in reduced cellular mass of FLT3, RAF, and AKT. The mass of another Hsp, Hsp70, was increased. The expression level of MLL-AF4 fusion protein was not reduced by 17-AAG in human leukemia cells. Conclusions: FLT3 + leukemias are sensitive to 17-AAG and Herbimycin A. 17-AAG inhibits leukemia cells with either FLT3-internal tandem duplication or wild-type FLT3, in part through destabilization of client kinases including FLT3, RAF, and AKT. 17-AAG is potentially useful for therapy of FLT3-expressing leukemias, including the mixed lineage leukemia fusion gene leukemias.