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

Liu Y, Hawkins OE, Su Y, Vilgelm AE, Sobolik T, Thu YM, Kantrow S, Splittgerber RC, Short S, Amiri KI, Ecsedy JA, Sosman JA, Kelley MC, Richmond A
EMBO Mol Med. 2013 5 (1): 149-66

PMID: 23180582 · PMCID: PMC3569660 · DOI:10.1002/emmm.201201378

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.

Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

MeSH Terms (25)

Animals Antineoplastic Agents Ataxia Telangiectasia Mutated Proteins Aurora Kinases Azepines Benzazepines Cell Cycle Proteins Cell Line, Tumor Cell Proliferation Cellular Senescence Checkpoint Kinase 2 DNA-Binding Proteins DNA Damage Humans Melanoma, Experimental Mice Mice, Nude NF-kappa B Polyploidy Protein-Serine-Threonine Kinases Protein Kinase Inhibitors Pyrimidines Tumor Suppressor Protein p53 Tumor Suppressor Proteins Xenograft Model Antitumor Assays

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