Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML.
To further investigate potential mechanisms of resistance to FLT3 inhibitors, we developed a resistant cell line by long-term culture of MV4-11 cells with ABT-869, designated as MV4-11-R. Gene profiling reveals up-regulation of FLT3LG (FLT3 ligand) and BIRC5 (survivin), but down-regulation of SOCS1, SOCS2, and SOCS3 in MV4-11-R cells. Hypermethylation of these SOCS genes leads to their transcriptional silencing. Survivin is directly regulated by STAT3. Stimulation of the parental MV4-11 cells with FLT3 ligand increases the expression of survivin and phosphorylated protein STAT1, STAT3, STAT5. Targeting survivin by short-hairpin RNA (shRNA) in MV4-11-R cells induces apoptosis and augments ABT-869-mediated cytotoxicity. Overexpression of survivin protects MV4-11 from apoptosis. Subtoxic dose of indirubin derivative (IDR) E804 resensitizes MV4-11-R to ABT-869 treatment by inhibiting STAT signaling activity and abolishing survivin expression. Combining IDR E804 with ABT-869 shows potent in vivo efficacy in the MV4-11-R xenograft model. Taken together, these results demonstrate that enhanced activation of STAT pathways and overexpression of survivin are important mechanisms of resistance to ABT-869, suggesting that the STAT pathways and survivin could be potential targets for reducing resistance developed in patients receiving FLT3 inhibitors.
Zhou
Jianbiao
J
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Bi
Chonglei
C
Janakakumara
Jasinghe V
JV
Liu
Shaw-Cheng
SC
Chng
Wee-Joo
WJ
Tay
Kian-Ghee
KG
Poon
Lai-Fong
LF
Xie
Zhigang
Z
Palaniyandi
Senthilnathan
S
Yu
Hanry
H
Glaser
Keith B
KB
Albert
Daniel H
DH
Davidsen
Steven K
SK
Chen
Chien-Shing
CS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity; D000077022:Survivin; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
C107489:BIRC5 protein, human; D004852:Epoxy Compounds; C496601:IDR-804; D007191:Indazoles; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D008869:Microtubule-Associated Proteins; D010671:Phenylurea Compounds; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012717:Sesquiterpenes; D000077022:Survivin; C513486:linifanib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3