Aarts, M., Bajrami, I., Herrera-Abreu, M. T., Elliott, R., Brough, R., Ashworth, A., Lord, C. J., Turner, N. C. (2015) Functional Genetic Screen Identifies Increased Sensitivity to WEE1 Inhibition in Cells with Defects in Fanconi Anemia and HR Pathways. MOLECULAR CANCER THERAPEUTICS, 14 (4). pp. 865-876. ISSN 1535-7163

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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. (C)2015 AACR.

Item Type:	Article
Authors (ICR Faculty only):	Turner, Nick and Lord, Chris and Ashworth, Alan
All Authors:	Aarts, M., Bajrami, I., Herrera-Abreu, M. T., Elliott, R., Brough, R., Ashworth, A., Lord, C. J., Turner, N. C.
Additional Information:	ISI Document Delivery No.: CM9TS Times Cited: 0 Cited Reference Count: 46 Aarts, Marieke Bajrami, Ilirjana Herrera-Abreu, Maria T. Elliott, Richard Brough, Rachel Ashworth, Alan Lord, Christopher J. Turner, Nicholas C. Cancer Research UK grant [A10038]; Netherlands Organisation for Scientific Research (NWO); Breakthrough Breast Cancer Research; NHS; ICR; Cancer Research UK [A10038]; Susan G. Komen for the Cure This work was supported by Cancer Research UK grant A10038, Susan G. Komen for the Cure, the Netherlands Organisation for Scientific Research (NWO; M. Aarts) and Breakthrough Breast Cancer Research. The authors acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and the ICR. M. Aarts, A. Ashworth, N.C. Turner were supported by Cancer Research UK (A10038) and Susan G. Komen for the Cure. M. Aarts was supported by the Netherlands Organisation for Scientific Research (NWO). I. Bajrami, M.T. Herrera-Abreu, R. Elliott, R. Brough, and C.J. Lord were supported by Breakthrough Breast Cancer Research. Amer assoc cancer research Philadelphia
Uncontrolled Keywords:	cancer susceptibility gene dna-damaging agents cross-link repair breast-cancer s-phase replication initiation genome integrity mitotic entry tumor-cells kinase
Research teams:	ICR divisions > Breast Cancer Research > Gene Function ICR divisions > Molecular Pathology > Gene Function ICR divisions > Breast Cancer Research > Molecular Oncology
Depositing User:	Alexander Smithson
Date Deposited:	10 Aug 2015 12:32
Last Modified:	10 Aug 2015 12:32
URI:	http://publications.icr.ac.uk/id/eprint/14283

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