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

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 - EMBO Mol Med (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.

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Targeting aurora kinases limits melanoma growthA,B. Biopsy tumour tissues from 19 melanoma patients were implanted into nude mice and when tumours formed they were passaged by implantation into treatment groups (n ≥ 4 mice per group). Tumour-bearing mice received MLN8054 (60 mg/kg) or vehicle alone (A), MLN8237 (30 mg/kg) or vehicle alone (B), once daily by oral gavage for 2–6 weeks depending on their response to the treatment or the tumour volume. Mean tumour volumes ± SEM are shown for patient V13 (A) or V35 (B) as representative patient tumours.C. Hs294T melanoma cells were injected subcutaneously into nude mice (2 × 106 cells per mouse). After 1 week, tumour-bearing mice were treated with vehicle control or MLN8237 (30 mg/kg) once daily for 28 days. Tumour volume was then evaluated to determine response to the drug. Mean tumour volumes ± SEM for five mice per treatment group are shown.D. Tissue microarray (TMA) slides from patient melanoma tumour implants growing on mice treated with vehicle control or MLN8237 were stained for pAURKA (T-288) (red), alpha tubulin (green) and DAPI (blue) to identify cells with p-AURKA associated with the nuclear spindle microtubule complex (yellow) (see insert enlargement in upper panel).E. Histological features of the H&E stained patient melanoma tissues from mice treated with vehicle or MLN8237.F. Ki67 (proliferation marker) staining of patient tissues from mice treated with MLN8237 or vehicle control.
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fig01: Targeting aurora kinases limits melanoma growthA,B. Biopsy tumour tissues from 19 melanoma patients were implanted into nude mice and when tumours formed they were passaged by implantation into treatment groups (n ≥ 4 mice per group). Tumour-bearing mice received MLN8054 (60 mg/kg) or vehicle alone (A), MLN8237 (30 mg/kg) or vehicle alone (B), once daily by oral gavage for 2–6 weeks depending on their response to the treatment or the tumour volume. Mean tumour volumes ± SEM are shown for patient V13 (A) or V35 (B) as representative patient tumours.C. Hs294T melanoma cells were injected subcutaneously into nude mice (2 × 106 cells per mouse). After 1 week, tumour-bearing mice were treated with vehicle control or MLN8237 (30 mg/kg) once daily for 28 days. Tumour volume was then evaluated to determine response to the drug. Mean tumour volumes ± SEM for five mice per treatment group are shown.D. Tissue microarray (TMA) slides from patient melanoma tumour implants growing on mice treated with vehicle control or MLN8237 were stained for pAURKA (T-288) (red), alpha tubulin (green) and DAPI (blue) to identify cells with p-AURKA associated with the nuclear spindle microtubule complex (yellow) (see insert enlargement in upper panel).E. Histological features of the H&E stained patient melanoma tissues from mice treated with vehicle or MLN8237.F. Ki67 (proliferation marker) staining of patient tissues from mice treated with MLN8237 or vehicle control.

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).


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

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 - EMBO Mol Med (2012)

Targeting aurora kinases limits melanoma growthA,B. Biopsy tumour tissues from 19 melanoma patients were implanted into nude mice and when tumours formed they were passaged by implantation into treatment groups (n ≥ 4 mice per group). Tumour-bearing mice received MLN8054 (60 mg/kg) or vehicle alone (A), MLN8237 (30 mg/kg) or vehicle alone (B), once daily by oral gavage for 2–6 weeks depending on their response to the treatment or the tumour volume. Mean tumour volumes ± SEM are shown for patient V13 (A) or V35 (B) as representative patient tumours.C. Hs294T melanoma cells were injected subcutaneously into nude mice (2 × 106 cells per mouse). After 1 week, tumour-bearing mice were treated with vehicle control or MLN8237 (30 mg/kg) once daily for 28 days. Tumour volume was then evaluated to determine response to the drug. Mean tumour volumes ± SEM for five mice per treatment group are shown.D. Tissue microarray (TMA) slides from patient melanoma tumour implants growing on mice treated with vehicle control or MLN8237 were stained for pAURKA (T-288) (red), alpha tubulin (green) and DAPI (blue) to identify cells with p-AURKA associated with the nuclear spindle microtubule complex (yellow) (see insert enlargement in upper panel).E. Histological features of the H&E stained patient melanoma tissues from mice treated with vehicle or MLN8237.F. Ki67 (proliferation marker) staining of patient tissues from mice treated with MLN8237 or vehicle control.
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fig01: Targeting aurora kinases limits melanoma growthA,B. Biopsy tumour tissues from 19 melanoma patients were implanted into nude mice and when tumours formed they were passaged by implantation into treatment groups (n ≥ 4 mice per group). Tumour-bearing mice received MLN8054 (60 mg/kg) or vehicle alone (A), MLN8237 (30 mg/kg) or vehicle alone (B), once daily by oral gavage for 2–6 weeks depending on their response to the treatment or the tumour volume. Mean tumour volumes ± SEM are shown for patient V13 (A) or V35 (B) as representative patient tumours.C. Hs294T melanoma cells were injected subcutaneously into nude mice (2 × 106 cells per mouse). After 1 week, tumour-bearing mice were treated with vehicle control or MLN8237 (30 mg/kg) once daily for 28 days. Tumour volume was then evaluated to determine response to the drug. Mean tumour volumes ± SEM for five mice per treatment group are shown.D. Tissue microarray (TMA) slides from patient melanoma tumour implants growing on mice treated with vehicle control or MLN8237 were stained for pAURKA (T-288) (red), alpha tubulin (green) and DAPI (blue) to identify cells with p-AURKA associated with the nuclear spindle microtubule complex (yellow) (see insert enlargement in upper panel).E. Histological features of the H&E stained patient melanoma tissues from mice treated with vehicle or MLN8237.F. Ki67 (proliferation marker) staining of patient tissues from mice treated with MLN8237 or vehicle control.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.

Show MeSH
Related in: MedlinePlus