title: Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML.
abstract: 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.
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Zhou
authors.forename: Chonglei
authors.initials: C
authors.lastname: Bi
authors.forename: Jasinghe V
authors.initials: JV
authors.lastname: Janakakumara
authors.forename: Shaw-Cheng
authors.initials: SC
authors.lastname: Liu
authors.forename: Wee-Joo
authors.initials: WJ
authors.lastname: Chng
authors.forename: Kian-Ghee
authors.initials: KG
authors.lastname: Tay
authors.forename: Lai-Fong
authors.initials: LF
authors.lastname: Poon
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xie
authors.forename: Senthilnathan
authors.initials: S
authors.lastname: Palaniyandi
authors.forename: Hanry
authors.initials: H
authors.lastname: Yu
authors.forename: Keith B
authors.initials: KB
authors.lastname: Glaser
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
mesh_terms: 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
chemical_list: 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