title: Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1.
abstract: Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. We show that WEE1 inhibition forces S-phase-arrested cells directly into mitosis without completing DNA synthesis, resulting in highly abnormal mitoses characterized by dispersed chromosomes and disorganized bipolar spindles, ultimately resulting in mitotic exit with gross micronuclei formation and apoptosis. This mechanism of cell death is shared by CHK1 inhibitors, and combined WEE1 and CHK1 inhibition forces mitotic entry from S-phase in the absence of chemotherapy. We show that p53/p21 inactivation combined with high expression of mitotic cyclins and EZH2 predispose to mitotic entry during S-phase with cells reliant on WEE1 to prevent premature cyclin-dependent kinase (CDK)1 activation. These features are characteristic of aggressive breast, and other, cancers for which WEE1 inhibitor combinations represent a promising targeted therapy.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research; Breast Unit, UK.
authors.forename: Marieke
authors.initials: M
authors.lastname: Aarts
authors.forename: Rachel
authors.initials: R
authors.lastname: Sharpe
authors.forename: Isaac
authors.initials: I
authors.lastname: Garcia-Murillas
authors.forename: Heidrun
authors.initials: H
authors.lastname: Gevensleben
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Hurd
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Shumway
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Turner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008938:Mitosis / Q000187:drug effects; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D063151:Polycomb Repressive Complex 2; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011744:Pyrimidinones; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D016196:S Phase / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D014157:Transcription Factors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011804:Quinolines; C512984:RO 3306; C495901:TP53 protein, human; D013844:Thiazoles; D013876:Thiophenes; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; D014508:Urea; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C549567:adavosertib; D000093542:Gemcitabine