ATR inhibition enables complete tumour regression in ALK-driven NB mouse models

Joanna Szydzik, Dan E. Lind, Badrul Arefin, Yeshwant Kurhe, Ganesh Umapathy, Joachim Tetteh Siaw, Arne Claeys, Jonatan L. Gabre, Jimmy Eynden (), Bengt Hallberg () and Ruth H. Palmer ()
Additional contact information
Joanna Szydzik: University of Gothenburg
Dan E. Lind: University of Gothenburg
Badrul Arefin: University of Gothenburg
Yeshwant Kurhe: University of Gothenburg
Ganesh Umapathy: University of Gothenburg
Joachim Tetteh Siaw: University of Gothenburg
Arne Claeys: Ghent University
Jonatan L. Gabre: University of Gothenburg
Jimmy Eynden: Ghent University
Bengt Hallberg: University of Gothenburg
Ruth H. Palmer: University of Gothenburg

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract High-risk neuroblastoma (NB) often involves MYCN amplification as well as mutations in ALK. Currently, high-risk NB presents significant clinical challenges, and additional therapeutic options are needed. Oncogenes like MYCN and ALK result in increased replication stress in cancer cells, offering therapeutically exploitable options. We have pursued phosphoproteomic analyses highlighting ATR activity in ALK-driven NB cells, identifying the BAY1895344 ATR inhibitor as a potent inhibitor of NB cell growth and proliferation. Using RNA-Seq, proteomics and phosphoproteomics we characterize NB cell and tumour responses to ATR inhibition, identifying key components of the DNA damage response as ATR targets in NB cells. ATR inhibition also produces robust responses in mouse models. Remarkably, a 2-week combined ATR/ALK inhibition protocol leads to complete tumor regression in two independent genetically modified mouse NB models. These results suggest that NB patients, particularly in high-risk groups with oncogene-induced replication stress, may benefit from ATR inhibition as therapeutic intervention.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-27057-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27057-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-27057-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().