These authors contributed equally to this work.
Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence
Article first published online: 25 NOV 2012
Copyright © 2013 EMBO Molecular Medicine
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 1, pages 149–166, January 2013
How to Cite
Liu, Y., Hawkins, O. E., Su, Y., Vilgelm, A. E., Sobolik, T., Thu, Y.-M., Kantrow, S., Splittgerber, R. C., Short, S., Amiri, K. I., Ecsedy, J. A., Sosman, J. A., Kelley, M. C. and Richmond, A. (2013), Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence. EMBO Mol Med, 5: 149–166. doi: 10.1002/emmm.201201378
- Issue published online: 3 JAN 2013
- Article first published online: 25 NOV 2012
- Manuscript Accepted: 11 OCT 2012
- Manuscript Revised: 8 OCT 2012
- Manuscript Received: 14 MAR 2012
- Funded Access
- aurora kinase;
- DNA damage;
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.