期刊
NATURE CANCER
卷 2, 期 3, 页码 312-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s43018-020-00171-8
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资金
- European Research council (AuroMYC)
- German Cancer Aid (Enable)
- Federal Ministry of Education and Research (DKTK)
- German Research Foundation (via DFG Research Group 2314)
- German Cancer Aid (via the Mildred Scheel Early Career Center)
- Cancer Research UK
- MRC [C1060/A16464]
- Department of Health (England) [C1060/A16464]
- Children with Cancer UK Research Fellowship
- German Research Foundation
- Wilhelm Sander Stiftung
- Children with Cancer UK Project [2014/174]
- Cancer Research UK Program Grants [C34648/A18339, C34648/A14610]
- Cancer Research UK Programme Award [C24461/A23302]
- MRC [MC_PC_18051, MC_PC_16047] Funding Source: UKRI
Aurora-A suppresses transcription-replication conflicts in MYCN-driven neuroblastoma, and combined inhibition of Aurora-A and ATR kinases leads to tumor regression in mouse models. MYCN activates Aurora-A, promotes histone phosphorylation, and suppresses transcription-replication conflicts.
Eilers and colleagues report that Aurora-A suppresses transcription-replication conflicts in MYCN-driven neuroblastoma, a vulnerability that can be targeted with a combination of Aurora-A and ATR kinase inhibitors. 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.
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