title: Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice.
abstract: Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.
authors.affiliation: Experimental Haematology Unit, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Amanda
authors.initials: A
authors.lastname: Nordigården
authors.forename: Jenny
authors.initials: J
authors.lastname: Zetterblad
authors.forename: Cecilia
authors.initials: C
authors.lastname: Trinks
authors.forename: Henrik
authors.initials: H
authors.lastname: Gréen
authors.forename: Pernilla
authors.initials: P
authors.lastname: Eliasson
authors.forename: Pia
authors.initials: P
authors.lastname: Druid
authors.forename: Kourosh
authors.initials: K
authors.lastname: Lotfi
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Walz
authors.forename: Jan-Ingvar
authors.initials: JI
authors.lastname: Jönsson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020080:Tandem Repeat Sequences; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D009025:Morpholines; D009363:Neoplasm Proteins; D018739:Oncogene Proteins v-erbB; D047428:Protein Kinase Inhibitors; C420268:Canertinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3