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

Yan Liu, Oriana E. Hawkins, Yingjun Su, Anna E. Vilgelm, Tammy Sobolik, Yee Mon Thu, Sara Kantrow, Ryan C Splittgerber, Sarah Short, Katayoun I. Amiri, Jeffery A. Ecsedy, Jeffery A. Sosman, Mark C. Kelley, Ann Richmond

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)149-166
Number of pages18
JournalEMBO Molecular Medicine
Volume5
Issue number1
DOIs
StatePublished - Jan 1 2013

Fingerprint

Aurora Kinases
DNA Damage
Growth
Pharmaceutical Preparations
Neoplasms
Melanoma
Phenotype
Polyploidy
Myeloid Cells
Oncogenes
Mitosis
Intercellular Signaling Peptides and Proteins
Cytokines

Keywords

  • Aurora kinase
  • DNA damage
  • Melanoma
  • NF-κB
  • Senescence

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence. / Liu, Yan; Hawkins, Oriana E.; Su, Yingjun; Vilgelm, Anna E.; Sobolik, Tammy; Thu, Yee Mon; Kantrow, Sara; Splittgerber, Ryan C; Short, Sarah; Amiri, Katayoun I.; Ecsedy, Jeffery A.; Sosman, Jeffery A.; Kelley, Mark C.; Richmond, Ann.

In: EMBO Molecular Medicine, Vol. 5, No. 1, 01.01.2013, p. 149-166.

Research output: Contribution to journalArticle

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 2013, 'Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence', EMBO Molecular Medicine, vol. 5, no. 1, pp. 149-166. https://doi.org/10.1002/emmm.201201378
Liu, Yan ; Hawkins, Oriana E. ; Su, Yingjun ; Vilgelm, Anna E. ; Sobolik, Tammy ; Thu, Yee Mon ; Kantrow, Sara ; Splittgerber, Ryan C ; Short, Sarah ; Amiri, Katayoun I. ; Ecsedy, Jeffery A. ; Sosman, Jeffery A. ; Kelley, Mark C. ; Richmond, Ann. / Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence. In: EMBO Molecular Medicine. 2013 ; Vol. 5, No. 1. pp. 149-166.
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