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

Abstract

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).

• Authors: Isabelle Roeschert, Evon Poon, Anton G Henssen, Heathcliff Dorado Garcia, Marco Gatti, Celeste Giansanti, Yann Jamin, Carsten P Ade, Peter Gallant, Christina Schülein-Völk, Petra Beli, Mark Richards, Mathias Rosenfeldt, Matthias Altmeyer, John Anderson, Angelika Eggert, Matthias Dobbelstein, Richard Bayliss, Louis Chesler, Gabriele Büchel, Martin Eilers
• Journal: Nature cancer (Nat Cancer) Vol. 2 Issue 3 Pg. 312-326 (03 2021) ISSN: 2662-1347 [Electronic] England
• PMID: 33768209 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• N-Myc Proto-Oncogene Protein
• Aurora Kinase A

Topics

• Animals
• Apoptosis (genetics)
• Aurora Kinase A (genetics)
• Cell Line, Tumor
• Mice
• N-Myc Proto-Oncogene Protein (genetics)
• Neuroblastoma (drug therapy)