Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence

Authors

  • Yan Liu,

    1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
    2. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Oriana E. Hawkins,

    1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
    2. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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    • These authors contributed equally to this work.

  • Yingjun Su,

    1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
    2. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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    • These authors contributed equally to this work.

  • Anna E. Vilgelm,

    1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
    2. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Tammy Sobolik,

    1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
    2. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Yee-Mon Thu,

    1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
    2. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Sara Kantrow,

    1. Division of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Ryan C. Splittgerber,

    1. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Sarah Short,

    1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
    2. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Katayoun I. Amiri,

    1. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Jeffery A. Ecsedy,

    1. Millennium Pharmaceuticals, Inc., Cambridge, MA, USA
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  • Jeffery A. Sosman,

    1. Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Mark C. Kelley,

    1. Division of Surgical Oncology, Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA
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  • Ann Richmond

    Corresponding author
    1. Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
    2. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
    • Tel: +1 615 343 7777; Fax: +1 615 936 2911

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Abstract

Oncogene-induced senescence can provide a protective mechanism against tumour progression. However, production of cytokines and growth factors by senescent cells may contribute to tumour development. Thus, it is unclear whether induction of senescence represents a viable therapeutic approach. Here, using a mouse model with orthotopic implantation of metastatic melanoma tumours taken from 19 patients, we observed that targeting aurora kinases with MLN8054/MLN8237 impaired mitosis, induced senescence and markedly blocked proliferation in patient tumour implants. Importantly, when a subset of tumour-bearing mice were monitored for tumour progression after pausing MLN8054 treatment, 50% of the tumours did not progress over a 12-month period. Mechanistic analyses revealed that inhibition of aurora kinases induced polyploidy and the ATM/Chk2 DNA damage response, which mediated senescence and a NF-κB-related, senescence-associated secretory phenotype (SASP). Blockade of IKKβ/NF-κB led to reversal of MLN8237-induced senescence and SASP. Results demonstrate that removal of senescent tumour cells by infiltrating myeloid cells is crucial for inhibition of tumour re-growth. Altogether, these data demonstrate that induction of senescence, coupled with immune surveillance, can limit melanoma growth.

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