Combined inhibition of Aurora-A and ATR kinases results in regression of MYCN-amplified neuroblastoma

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Item Type:	Article
Title:	Combined inhibition of Aurora-A and ATR kinases results in regression of MYCN-amplified neuroblastoma
Creators Name:	Roeschert, I., Poon, E., Henssen, A.G., Dorado Garcia, H., Gatti, M., Giansanti, C., Jamin, Y., Ade, C.P., Gallant, P., Schülein-Völk, C., Beli, P., Richards, M., Rosenfeldt, M., Altmeyer, M., Anderson, J., Eggert, A., Dobbelstein, M., Bayliss, R., Chesler, L., Büchel, G. and Eilers, M.
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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