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    Olaparib-induced Adaptive Response Is Disrupted by FOXM1 Targeting that Enhances Sensitivity to PARP Inhibition

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    Fang_2019.pdf (1.305Mb)
    Issue Date
    2018-06-01
    Author
    Fang, Pingping
    Madden, Jill A.
    Neums, Lisa
    Moulder, Ryan Kenneth
    Forrest, M. Laird
    Chien, Jeremy
    Publisher
    American Association for Cancer Research
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    ©2018 AACR
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    Abstract
    FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in PARP inhibitor response has not yet been studied. This study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. On the basis of ChIP-qPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair. FOXM1 knockdown by RNAi or inhibition by thiostrepton decreases FOXM1 expression, decreases the expression of HR repair genes, such as BRCA1 and RAD51, and enhances sensitivity to olaparib. Comet and PARP trapping assays revealed increases in DNA damage and PARP trapping in FOXM1-inhibited cells treated with olaparib. Finally, thiostrepton decreases the expression of BRCA1 in rucaparib-resistant cells and enhances sensitivity to rucaparib. Collectively, these results identify that FOXM1 plays an important role in the adaptive response induced by olaparib and FOXM1 inhibition by thiostrepton induces “BRCAness” and enhances sensitivity to PARP inhibitors.
    URI
    http://hdl.handle.net/1808/29687
    DOI
    https://doi.org/10.1158/1541-7786.MCR-17-0607
    Collections
    • Pharmaceutical Chemistry Scholarly Works [343]
    Citation
    Fang, P., Madden, J. A., Neums, L., Moulder, R. K., Forrest, M. L., & Chien, J. (2018). Olaparib-induced Adaptive Response Is Disrupted by FOXM1 Targeting that Enhances Sensitivity to PARP Inhibition. Molecular cancer research : MCR, 16(6), 961–973. doi:10.1158/1541-7786.MCR-17-0607

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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