| First Author | Roeschert I | Year | 2021 |
| Journal | Nat Cancer | Volume | 2 |
| Issue | 3 | Pages | 312-326 |
| PubMed ID | 33768209 | Mgi Jnum | J:313873 |
| Mgi Id | MGI:6706374 | Doi | 10.1038/s43018-020-00171-8 |
| Citation | Roeschert I, et al. (2021) Combined inhibition of Aurora-A and ATR kinase results in regression of MYCN-amplified neuroblastoma. Nat Cancer 2(3):312-326 |
| abstractText | 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). |
