title: CHK1 and WEE1 inhibition combine synergistically to enhance therapeutic efficacy in acute myeloid leukemia ex vivo.
abstract: Novel combinations targeting new molecular vulnerabilities are needed to improve the outcome of patients with acute myeloid leukemia. We recently identified WEE1 kinase as a novel target in leukemias. To identify genes that are synthetically lethal with WEE1 inhibition, we performed a short interfering RNA screen directed against cell cycle and DNA repair genes during concurrent treatment with the WEE1 inhibitor MK1775. CHK1 and ATR, genes encoding two replication checkpoint kinases, were among the genes whose silencing enhanced the effects of WEE1 inhibition most, whereas CDK2 short interfering RNA antagonized MK1775 effects. Building on this observation, we examined the impact of combining MK1775 with selective small molecule inhibitors of CHK1, ATR and cyclin-dependent kinases. The CHK1 inhibitor MK8776 sensitized acute myeloid leukemia cell lines and primary leukemia specimens to MK1775 ex vivo, whereas smaller effects were observed with the MK1775/MK8776 combination in normal myeloid progenitors. The ATR inhibitor VE-821 likewise enhanced the antiproliferative effects of MK1775, whereas the cyclin-dependent kinase inhibitor roscovitine antagonized MK1775. Further studies showed that MK8776 enhanced MK1775-mediated activation of the ATR/CHK1 pathway in acute leukemia cell lines and ex vivo. These results indicate that combined cell cycle checkpoint interference with MK1775/MK8776 warrants further investigation as a potential treatment for acute myeloid leukemia.
authors.affiliation: tibes.raoul@mayo.edu.
authors.forename: Leena
authors.initials: L
authors.lastname: Chaudhuri
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Vincelette
authors.forename: Brian D
authors.initials: BD
authors.lastname: Koh
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Naylor
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Amanda
authors.initials: A
authors.lastname: McNally
authors.forename: Ivana
authors.initials: I
authors.lastname: Gojo
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
authors.forename: Lisa O
authors.initials: LO
authors.lastname: Sproat
authors.forename: James M
authors.initials: JM
authors.lastname: Bogenberger
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014410:Tumor Stem Cell Assay
chemical_list: D018797:Cell Cycle Proteins; C559815:MK-8776; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D034741:RNA, Small Interfering; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C549567:adavosertib