Top-Performer: Role of the MYCN Oncogene in Neuroblastoma

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Oncotarget

Oncotarget published this priority research paper on June 9, 2020, entitled, “MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma,” by researchers from the United Kingdom’s University of Sheffield, Institute of Cancer Research, Royal Marsden NHS Trust, Sheffield Children’s Hospital, and University of Cambridge. Abstract: This study investigates the influence expression of the MYCN oncogene has on the DNA damage response, replication fork progression and sensitivity to PARP inhibition in neuroblastoma. In a panel of neuroblastoma cell lines, MYCN amplification or MYCN expression resulted in increased cell death in response to a range of PARP inhibitors (niraparib, veliparib, talazoparib and olaparib) compared to the response seen in non-expressing/amplified cells. MYCN expression slowed replication fork speed and increased replication fork stalling, an effect that was amplified by PARP inhibition or PARP1 depletion. Increased DNA damage seen was specifically induced in S-phase cells. Importantly, PARP inhibition caused a significant increase in the survival of mice bearing MYCN expressing tumours in a transgenic murine model of MYCN expressing neuroblastoma. Olaparib also sensitized MYCN expressing cells to camptothecin- and temozolomide-induced cell death to a greater degree than non-expressing cells. In summary, MYCN expression leads to increased replication stress in neuroblastoma cells. This effect is exaggerated by inhibition of PARP, resulting in S-phase specific DNA damage and ultimately increased tumour cell death. PARP inhibition alone or in combination with classical chemotherapeutics is therefore a potential therapeutic strategy for neuroblastoma and may be more effective in MYCN expressing tumours. To date, this priority research paper has generated an Altmetric Attention Score of 58. The Altmetric Attention Score provides an at-a-glance indication of the volume and type of online attention the research has received. Top Oncotarget publications rated by Altmetric Attention Score - https://www.oncotarget.com/news/altmetric/ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.27329 DOI - https://doi.org/10.18632/oncotarget.27329 Full text - https://www.oncotarget.com/article/27329/text/ Correspondence to - Helen E. Bryant - h.bryant@sheffield.ac.uk and Louis Chesler - louis.chesler@icr.ac.uk Keywords - PARP inhibitor, neuroblastoma, MYCN, replication stress, replication fork stalling About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget YouTube - https://www.youtube.com/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957