Helmholtz Gemeinschaft


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

Item Type:Article
Title:Combined inhibition of Aurora-A and ATR kinases results in regression of MYCN-amplified neuroblastoma
Creators Name:Roeschert, I. and Poon, E. and Henssen, A.G. and Dorado Garcia, H. and Gatti, M. and Giansanti, C. and Jamin, Y. and Ade, C.P. and Gallant, P. and Schülein-Völk, C. and Beli, P. and Richards, M. and Rosenfeldt, M. and Altmeyer, M. and Anderson, J. and Eggert, A. and Dobbelstein, M. and Bayliss, R. and Chesler, L. and 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
Publisher:Springer Nature
Page Range:312-326
Date:March 2021
Official Publication:https://doi.org/10.1038/s43018-020-00171-8
PubMed:View item in PubMed

Repository Staff Only: item control page

Open Access
MDC Library