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

EMBO Molecular Medicine

Yan Liu¹  Oriana E. Hawkins¹  Yingjun Su¹  Anna E. Vilgelm¹  Tammy Sobolik¹  Yee-Mon Thu¹  Sara Kantrow⁶  Ryan C. Splittgerber⁴  Sarah Short¹  Katayoun I. Amiri⁴  Jeffery A. Ecsedy³  Jeffery A. Sosman²  Mark C. Kelley⁵ 

[1] Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA;Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA;Millennium Pharmaceuticals, Inc., Cambridge, MA, USA;Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA;Division of Surgical Oncology, Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA;Division of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA

关键词: aurora kinase;    DNA damage;    melanoma;    NF‐κB;    senescence;   

DOI  :  10.1002/emmm.201201378

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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