title: 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.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Oriana E
authors.initials: OE
authors.lastname: Hawkins
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Su
authors.forename: Anna E
authors.initials: AE
authors.lastname: Vilgelm
authors.forename: Tammy
authors.initials: T
authors.lastname: Sobolik
authors.forename: Yee-Mon
authors.initials: YM
authors.lastname: Thu
authors.forename: Sara
authors.initials: S
authors.lastname: Kantrow
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Splittgerber
authors.forename: Sarah
authors.initials: S
authors.lastname: Short
authors.forename: Katayoun I
authors.initials: KI
authors.lastname: Amiri
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Ecsedy
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kelley
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D064127:Aurora Kinases; D001381:Azepines / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D001552:Benzazepines; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C550258:MLN 8237; C518940:MLN8054; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D064127:Aurora Kinases; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases