title: Functional Genetic Screen Identifies Increased Sensitivity to WEE1 Inhibition in Cells with Defects in Fanconi Anemia and HR Pathways.
abstract: WEE1 kinase regulates CDK1 and CDK2 activity to facilitate DNA replication during S-phase and to prevent unscheduled entry into mitosis. WEE1 inhibitors synergize with DNA-damaging agents that arrest cells in S-phase by triggering direct mitotic entry without completing DNA synthesis, resulting in catastrophic chromosome fragmentation and apoptosis. Here, we investigated how WEE1 inhibition could be best exploited for cancer therapy by performing a functional genetic screen to identify novel determinants of sensitivity to WEE1 inhibition. Inhibition of kinases that regulate CDK activity, CHK1 and MYT1, synergized with WEE1 inhibition through both increased replication stress and forced mitotic entry of S-phase cells. Loss of multiple components of the Fanconi anemia (FA) and homologous recombination (HR) pathways, in particular DNA helicases, sensitized to WEE1 inhibition. Silencing of FA/HR genes resulted in excessive replication stress and nucleotide depletion following WEE1 inhibition, which ultimately led to increased unscheduled mitotic entry. Our results suggest that cancers with defects in FA and HR pathways may be targeted by WEE1 inhibition, providing a basis for a novel synthetic lethal strategy for cancers harboring FA/HR defects.
authors: CRUK Gene Function Laboratory, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors: Marieke
authors: M
authors: Aarts
authors: CRUK Gene Function Laboratory, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors: Ilirjana
authors: I
authors: Bajrami
authors: CRUK Gene Function Laboratory, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors: Maria T
authors: MT
authors: Herrera-Abreu
authors: CRUK Gene Function Laboratory, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors: Richard
authors: R
authors: Elliott
authors: CRUK Gene Function Laboratory, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors: Rachel
authors: R
authors: Brough
authors: CRUK Gene Function Laboratory, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors: Alan
authors: A
authors: Ashworth
authors: CRUK Gene Function Laboratory, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors: Christopher J
authors: CJ
authors: Lord
authors: CRUK Gene Function Laboratory, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom. Breast Unit, Royal Marsden Hospital, London, United Kingdom. nicholas.turner@icr.ac.uk.
authors: Nicholas C
authors: NC
authors: Turner
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins; D015870:Gene Expression; D059765:Homologous Recombination; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; C078341:MYT1 protein, human; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D014157:Transcription Factors; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C518295:FANCM protein, human; D004265:DNA Helicases; C000618935:BRIP1 protein, human; D020365:RNA Helicases