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

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.

• Authors: 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
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 5 Issue 1 Pg. 149-66 (01 2013) ISSN: 1757-4684 [Electronic] England
• PMID: 23180582 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Chemical References

• Antineoplastic Agents
• Azepines
• Benzazepines
• Cell Cycle Proteins
• DNA-Binding Proteins
• MLN 8237
• MLN8054
• NF-kappa B
• Protein Kinase Inhibitors
• Pyrimidines
• TP53 protein, human
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• Checkpoint Kinase 2
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Atm protein, mouse
• Aurora Kinases
• CHEK2 protein, human
• Chek2 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Ataxia Telangiectasia Mutated Proteins
• Aurora Kinases
• Azepines (pharmacology)
• Benzazepines (pharmacology)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cellular Senescence (drug effects)
• Checkpoint Kinase 2
• DNA Damage
• DNA-Binding Proteins (metabolism)
• Humans
• Melanoma, Experimental (drug therapy, metabolism, pathology, secondary)
• Mice
• Mice, Nude
• NF-kappa B (antagonists & inhibitors)
• Polyploidy
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pyrimidines (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)
• Tumor Suppressor Proteins (metabolism)
• Xenograft Model Antitumor Assays