DNA-PK mediates AKT activation and apoptosis inhibition in clinically acquired platinum resistance

Euan A. Stronach, Michelle Chen, Elaina N. Maginn, Roshan Agarwal, Gordon B. Mills, Harpreet Wasan, Hani Gabra

    Research output: Contribution to journalArticle

    82 Scopus citations

    Abstract

    Clinical resistance to chemotherapy is a frequent event in cancer treatment and is closely linked to poor outcome. High-grade serous (HGS) ovarian cancer is characterized by p53 mutation and high levels of genomic instability. Treatment includes platinum-based chemotherapy and initial response rates are high; however, resistance is frequently acquired, at which point treatment options are largely palliative. Recent data indicate that platinumresistant clones exist within the sensitive primary tumor at presentation, implying resistant cell selection after treatment with platinum chemotherapy. The AKT pathway is central to cell survival and has been implicated in platinum resistance. Here, we show that platinum exposure induces an AKT-dependent, prosurvival, DNA damage response in clinically platinum-resistant but not platinum-sensitive cells. AKT relocates to the nucleus of resistant cells where it is phosphorylated specifically on S473 by DNA-dependent protein kinase (DNA-PK), and this activation inhibits cisplatin-mediated apoptosis. Inhibition of DNA-PK or AKT, but not mTORC2, restores platinum sensitivity in a panel of clinically resistant HGS ovarian cancer cell lines: we also demonstrate these effects in other tumor types. Resensitization is associated with prevention of AKT-mediated BAD phosphorylation. Strikingly, in patient-matched sensitive cells, we do not see enhanced apoptosis on combining cisplatin with AKT or DNA-PK inhibition. Insulinmediated activation of AKT is unaffected by DNA-PK inhibitor treatment, suggesting that this effect is restricted to DNA damage-mediated activation of AKT and that, clinically, DNA-PK inhibition might prevent platinum-induced AKT activation without interfering with normal glucose homeostasis, an unwanted toxicity of direct AKT inhibitors.

    Original languageEnglish (US)
    Pages (from-to)1069-1080
    Number of pages12
    JournalNeoplasia
    Volume13
    Issue number11
    DOIs
    StatePublished - Nov 2011

    ASJC Scopus subject areas

    • Cancer Research

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  • Cite this

    Stronach, E. A., Chen, M., Maginn, E. N., Agarwal, R., Mills, G. B., Wasan, H., & Gabra, H. (2011). DNA-PK mediates AKT activation and apoptosis inhibition in clinically acquired platinum resistance. Neoplasia, 13(11), 1069-1080. https://doi.org/10.1593/neo.111032