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| Item Type: | Article |
|---|---|
| Title: | Combined inhibition of Aurora-A and ATR kinases results in regression of MYCN-amplified neuroblastoma |
| Creators: |
Roeschert, I., Poon, E.  ORCID: https://orcid.org/0000-0002-0616-2487, Henssen, A.G. ORCID: https://orcid.org/0000-0003-1534-778X, Dorado Garcia, H. ORCID: https://orcid.org/0000-0002-2578-3350, Gatti, M., Giansanti, C. ORCID: https://orcid.org/0000-0003-3229-8385, Jamin, Y. ORCID: https://orcid.org/0000-0003-0350-3757, Ade, C.P. ORCID: https://orcid.org/0000-0001-7226-1179, Gallant, P., Schülein-Völk, C., Beli, P. ORCID: https://orcid.org/0000-0001-9507-9820, Richards, M. ORCID: https://orcid.org/0000-0003-1108-2825, Rosenfeldt, M., Altmeyer, M. ORCID: https://orcid.org/0000-0003-3780-1170, Anderson, J., Eggert, A., Dobbelstein, M., Bayliss, R. ORCID: https://orcid.org/0000-0003-0604-2773, Chesler, L. ORCID: https://orcid.org/0000-0001-7842-2068, Büchel, G. ORCID: https://orcid.org/0000-0001-7070-7341 and Eilers, M. ORCID: https://orcid.org/0000-0002-0376-6533
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| Abstract: | Amplification of MYCN is the driving oncogenic change in a subset of high-risk neuroblastomas. The MYCN protein and the Aurora-A kinase form a complex during the S phase that stabilizes MYCN. Here we show that MYCN activates Aurora-A on chromatin, which phosphorylates histone H3 at serine 10 in the S phase, promotes the deposition of histone H3.3 and suppresses R-loop formation. Inhibition of Aurora-A induces transcription–replication conflicts and activates ataxia telangiectasia and Rad3-related (ATR) kinase, which limits double-strand break accumulation upon Aurora-A inhibition. Combined inhibition of Aurora-A and ATR kinases induces rampant tumor-specific apoptosis and tumor regression in mouse models of neuroblastoma, leading to permanent eradication in a subset of mice. The therapeutic efficacy is due to both tumor cell-intrinsic and immune cell-mediated mechanisms. We propose that targeting the ability of Aurora-A to resolve transcription–replication conflicts is an effective therapy for MYCN-driven neuroblastoma. |
| Keywords: | Apoptosis, Aurora Kinase A, N-Myc Proto-Oncogene Protein, Neuroblastoma, Tumor Cell Line, Animals, Mice |
| Source: | Nature Cancer |
| ISSN: | 2662-1347 |
| Publisher: | Springer Nature |
| Volume: | 2 |
| Number: | 3 |
| Page Range: | 312-326 |
| Date: | March 2021 |
| Additional Information: | Copyright © The Author(s), under exclusive licence to Springer Nature America, Inc. 2021 |
| Official Publication: | https://doi.org/10.1038/s43018-020-00171-8 |
| External Fulltext: | View full text on PubMed Central |
| PubMed: | View item in PubMed |
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