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 extend our findings in vivo, we treated patient tumour-bearing mice with vehicle, IKKβ inhibitor (BMS345541 100 mg/kg daily), aurora kinase inhibitor (MLN8237 30 mg/kg daily), or both. After treatment, we observed no synergistic effects with combined treatment (Fig 9A). H&E staining demonstrated that disruption of IKKβ/NF-κB bypasses aurora kinase inhibitor-induced senescence (Fig 9B). Similar results were obtained in Hs294T-bearing mice with the same treatment (Fig 9C). Since BMS345541 treatment induces cell death, we reduced the dose of BMS345541 from 100 to 75 mg/kg once daily. When 75 mg/kg of BMS345541 was administered, we found that combined treatment impaired the growth inhibitory response compared to treatment with either single agent alone (Fig 9D).
Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.