Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.
Bottom Line: 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.Altogether, these data demonstrate that induction of senescence, coupled with immune surveillance, can limit melanoma growth.
Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.Show MeSH
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Mentions: To determine whether targeting aurora kinase can inhibit melanoma growth in vivo, we implanted surgically resected tumours from melanoma patients into Fox nu/nu mice and then propagated tumours from the 19 patients whose tumour grew in mice by transplantation into additional Fox nu/nu mice. Tumour-bearing mice received oral doses of AURKA inhibitors, MLN8054 (60 mg/kg, QD), MLN8237 (30 mg/kg, QD) or vehicle control once daily. Substantial and significant inhibition of tumour growth was observed in implants from 18 of 19 patients. Representative graphs of the growth response to MLN8054 or MLN8237 are shown in Fig 1A and B. Graphs depicting growth response curves of all other patient tumour implants are presented in Supporting Information Figs S2 and S3. In addition to patient melanoma tissues, we also investigated the effects of MLN8237 on the growth of Hs294T metastatic melanoma cell line xenografts. There was a 70% decrease in tumour volume in MLN8237-treated mice compared to vehicle control-treated mice (Fig 1C).
Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.