title: Evaluation of checkpoint kinase targeting therapy in acute myeloid leukemia with complex karyotype.
abstract: There has been considerable interest in targeting cell cycle checkpoints particularly in emerging and alternative anticancer strategies. Here, we show that checkpoint abrogation by AZD7762, a potent and selective CHK1/2 kinase inhibitor enhances genotoxic treatment efficacy in immature KG1a leukemic cell line and in AML patient samples, particularly those with a complex karyotype, which display major genomic instability and chemoresistance. Furthermore, these data suggest that constitutive DNA-damage level might be useful markers to select AML patients susceptible to receive checkpoint inhibitor in combination with conventional chemotherapy. Moreover, this study demonstrates for the first time that AZD7762 inhibitor targets the CD34(+)CD38(-)CD123(+) primitive leukemic progenitors, which are responsible for the majority of AML patients relapse. Finally, CHK1 inhibition does not seem to affect clonogenic potential of normal hematopoietic progenitors.
authors.affiliation: INSERM, U1037, Cancer Research Center of Toulouse, CNRS ERL 5294, Toulouse, France. christine.didier@inserm.fr
authors.forename: Christine
authors.initials: C
authors.lastname: Didier
authors.forename: Cécile
authors.initials: C
authors.lastname: Demur
authors.forename: Fanny
authors.initials: F
authors.lastname: Grimal
authors.forename: Denis
authors.initials: D
authors.lastname: Jullien
authors.forename: Stéphane
authors.initials: S
authors.lastname: Manenti
authors.forename: Bernard
authors.initials: B
authors.lastname: Ducommun
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D047428:Protein Kinase Inhibitors; D013876:Thiophenes; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1