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

Szydzik, Joanna ; Lind, Dan E. ; Arefin, Badrul ; Kurhe, Yeshwant ; Umapathy, Ganesh ; Siaw, Joachim Tetteh LU orcid ; Claeys, Arne ; Gabre, Jonatan L. ; Van den Eynden, Jimmy and Hallberg, Bengt , et al. (2021) In Nature Communications 12(1). p.1-18
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
in
Nature Communications
volume
12
issue
1
article number
6813
pages
1 - 18
publisher
Nature Publishing Group
external identifiers
  • scopus:85119827314
  • pmid:34819497
ISSN
2041-1723
DOI
10.1038/s41467-021-27057-2
language
English
LU publication?
no
additional info
Publisher Copyright: © 2021, The Author(s).
id
f78f145e-48b2-4578-8771-f9bea889b62b
date added to LUP
2025-03-19 11:49:47
date last changed
2025-06-25 20:10:22
@article{f78f145e-48b2-4578-8771-f9bea889b62b,
  abstract     = {{<p>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.</p>}},
  author       = {{Szydzik, Joanna and Lind, Dan E. and Arefin, Badrul and Kurhe, Yeshwant and Umapathy, Ganesh and Siaw, Joachim Tetteh and Claeys, Arne and Gabre, Jonatan L. and Van den Eynden, Jimmy and Hallberg, Bengt and Palmer, Ruth H.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{1--18}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{ATR inhibition enables complete tumour regression in ALK-driven NB mouse models}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-27057-2}},
  doi          = {{10.1038/s41467-021-27057-2}},
  volume       = {{12}},
  year         = {{2021}},
}