• Open Access

Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53

Authors

  • Chris T. Williamson,

    1. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
    2. Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada
    3. Present address: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire, UK
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  • Eiji Kubota,

    1. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
    2. Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada
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  • Jeffrey D. Hamill,

    1. Cancer Therapeutics Program, Ottawa Hospital Research Institute, Departments of Medicine and Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada
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  • Alexander Klimowicz,

    1. Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada
    2. Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada
    3. Functional Tissue Imaging Unit, Tom Baker Cancer Centre, Calgary, Alberta, Canada
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  • Ruiqiong Ye,

    1. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
    2. Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada
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  • Huong Muzik,

    1. Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada
    2. Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada
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  • Michelle Dean,

    1. Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada
    2. Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada
    3. Functional Tissue Imaging Unit, Tom Baker Cancer Centre, Calgary, Alberta, Canada
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  • LiRen Tu,

    1. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
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  • David Gilley,

    1. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Anthony M. Magliocco,

    1. Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada
    2. Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada
    3. Functional Tissue Imaging Unit, Tom Baker Cancer Centre, Calgary, Alberta, Canada
    4. Department of Oncology, University of Calgary, Calgary, Alberta, Canada
    5. Present address: H. Lee Moffit Cancer Center, Tampa, FL, USA
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  • Bruce C. McKay,

    1. Cancer Therapeutics Program, Ottawa Hospital Research Institute, Departments of Medicine and Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada
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  • D. Gwyn Bebb,

    Corresponding author
    1. Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada
    2. Functional Tissue Imaging Unit, Tom Baker Cancer Centre, Calgary, Alberta, Canada
    3. Department of Oncology, University of Calgary, Calgary, Alberta, Canada
    • D. Gwyn Bebb, Tel: +1 403 521 3166; Fax: +1 403 283 1651

      Susan P. Lees-Miller, Tel: +1 403 220 7628; Fax: +1 403 283 8727

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  • Susan P. Lees-Miller

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
    2. Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada
    3. Department of Oncology, University of Calgary, Calgary, Alberta, Canada
    • D. Gwyn Bebb, Tel: +1 403 521 3166; Fax: +1 403 283 1651

      Susan P. Lees-Miller, Tel: +1 403 220 7628; Fax: +1 403 283 8727

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Abstract

Poly-ADP ribose polymerase (PARP) inhibitors have shown promise in the treatment of human malignancies characterized by deficiencies in the DNA damage repair proteins BRCA1 and BRCA2 and preclinical studies have demonstrated the potential effectiveness of PARP inhibitors in targeting ataxia-telangiectasia mutated (ATM)-deficient tumours. Here, we show that mantle cell lymphoma (MCL) cells deficient in both ATM and p53 are more sensitive to the PARP inhibitor olaparib than cells lacking ATM function alone. In ATM-deficient MCL cells, olaparib induced DNA-PK-dependent phosphorylation and stabilization of p53 as well as expression of p53-responsive cell cycle checkpoint regulators, and inhibition of DNA-PK reduced the toxicity of olaparib in ATM-deficient MCL cells. Thus, both DNA-PK and p53 regulate the response of ATM-deficient MCL cells to olaparib. In addition, small molecule inhibition of both ATM and PARP was cytotoxic in normal human fibroblasts with disruption of p53, implying that the combination of ATM and PARP inhibitors may have utility in targeting p53-deficient malignancies.

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