Open AccessCombined inhibition of Aurora-A and ATR kinases results in regression of MYCN-amplified neuroblastoma
Author(s) -
Isabelle Roeschert,
Evon Poon,
Anton G. Henssen,
Heathcliff Dorado García,
Marco Gatti,
Celeste Giansanti,
Yann Jamin,
Carsten P. Ade,
Peter Gallant,
Christina Schülein-Völk,
Petra Beli,
Mark W. Richards,
Mathias T. Rosenfeldt,
Matthias Altmeyer,
John Anderson,
Angelika Eggert,
Matthias Dobbelstein,
Richard Bayliss,
Louis Chesler,
Gabriele Büchel,
Martin Eilers
Publication year - 2021
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-00171-8
Subject(s) - neuroblastoma , aurora kinase , cancer research , aurora inhibitor , chromatin , kinase , biology , histone h3 , histone , aurora a kinase , microbiology and biotechnology , cell cycle , apoptosis , genetics , dna , cell culture
Amplification of MYCN is the driving oncogene in a subset of high-risk neuroblastoma. The MYCN protein and the Aurora-A kinase form a complex during S phase that stabilizes MYCN. Here we show that MYCN activates Aurora-A on chromatin, which phosphorylates histone H3 at serine 10 in S phase, promotes the deposition of histone H3.3 and suppresses R-loop formation. Inhibition of Aurora-A induces transcription-replication conflicts and activates the Ataxia telangiectasia and Rad3 related (ATR) kinase, which limits double-strand break accumulation upon Aurora-A inhibition. Combined inhibition of Aurora-A and ATR 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 (141 words).