Replication-stress induced mitotic aberrancies in cancer biology

    Research output: ThesisThesis fully internal (DIV)

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    Abstract

    One of the most important challenges in the treatment of cancer is to obtain successful tumor clearance, while at the same time making sure that healthy tissues remain unharmed. To achieve this, a better understanding of tumor-specific properties is required to uncover tumor-selective treatments. One example of such a strategy is the specific cytotoxic effect of PARP inhibitors in tumors harboring mutations in the BRCA1 or BRCA2 genes. However, how PARP inhibitors exert their effects remains unclear.
    In this thesis, we show PARP inhibitors to impair replication fork stability in homologous recombination (HR)-deficient cancer cells. Furthermore, we show that replication-born lesions are transmitted into mitosis, resulting in mitotic defects, including the formation of chromatin bridges during anaphase. If left unresolved, chromatin bridges lead to cytokinesis failure. Our findings indicate that mitotic progression is essential for PARP inhibitor cytotoxicity. Furthermore, we show that ATR inhibition potentiates PARP inhibitor treatment in HR-deficient cells, which was related to a role for ATR in regulating cell cycle control. Indeed, ATR inhibition induced premature mitotic entry, enhancing chromatin bridges and lagging chromosomes.
    Mitotic aberrancies are not only observed following PARP inhibitor treatment. We observed that also oncogene-induced replication stress impaired the ability of cells to properly distribute chromosomes over daughter cells. Interestingly, cells harboring oncogene-induced mitotic aberrancies were highly sensitive to inhibition of checkpoint kinases ATR and WEE1.
    For this reason, the findings presented in this thesis could aid in the selective killing of cancer cells by specific targeting of cells with replication stress-induced mitotic aberrancies.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • van Vugt, Marcel, Supervisor
    • Foijer, Floris, Co-supervisor
    • de Jong, Steven, Assessment committee
    • Calkhoven, Cor, Assessment committee
    • de Bruin, A., Assessment committee, External person
    Award date22-May-2019
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-034-1631-1
    Electronic ISBNs978-94-034-1630-4
    Publication statusPublished - 2019

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