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

Nat Cancer. 2021 Mar;2(3):312-326. doi: 10.1038/s43018-020-00171-8. Epub 2021 Feb 11.


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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