Human leukemias with mutated FLT3 kinase are synergistically sensitive to FLT3 and Hsp90 inhibitors: the key role of the STAT5 signal transduction pathway.
17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of the molecular chaperone heat shock protein 90, results in cell type-specific inhibition of proliferation of leukemic cells. GTP14564 is a tyrosine kinase inhibitor actively against FLT3. The current study evaluated the single and combined effects of 17-AAG and GTP14564, and the role of FLT3 in their inhibitory effects. The importance of FLT3 mutations was demonstrated using small interfering RNA (siRNA) targeted to FLT3. Similar to FLT3 siRNA, GTP14564 inhibited FLT3 internal tandem duplication (ITD) cells (MV4;11) and FLT3 amplified wild-type cells (SEMK2-M1), but not wild-type FLT3 cells (RS4;11). However, when RS4;11 cells were stimulated with FLT3-ligand, phosphorylation of STAT5 and GTP14564 inhibition were observed. Responses to GTP14564 in all cell types were directly related to the level of STAT5 phosphorylation in the cells. We observed synergistic effects of combined 17-AAG and GTP14564 in cell lines with FLT3-ITD and amplified wild-type FLT3. Combined treatment with 17-AAG and GTP14564 reduced the levels of p-FLT3 and p-STAT5, enhanced G0/G1 arrest and apoptosis in FLT3-ITD and amplified wild-type FLT3. The combination of 17-AAG with FLT3 kinase inhibitors can enhance targeted therapy in leukemias with FLT3 mutations, such as MLL fusion gene leukemias.
Yao
Q
Q
The Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Nishiuchi
R
R
Kitamura
T
T
Kersey
J H
JH
D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology; D016227:Benzoquinones; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008894:Milk Proteins / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000187:drug effects / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D017828:Rifabutin / Q000031:analogs & derivatives / Q000494:pharmacology; D050799:STAT5 Transcription Factor; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3
D001572:Benzofurans; D016227:Benzoquinones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C477524:GTP 14564; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D017828:Rifabutin; C112765:tanespimycin; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3