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

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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. Effective therapeutic options are still needed in neuroblastoma treatment. Here, the authors, through a comprehensive proteomics analysis, identify ATR as a potential therapeutic target of neuroblastoma and demonstrate the efficacy of the ATR inhibitor BAY1895344 in combination with the ALK tyrosine kinase inhibitor lorlatinib.
Keywords
General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, DEOXYCYTIDINE KINASE, GENE ATR, NEUROBLASTOMA, CANCER, REVEALS, CHECKPOINT, LANDSCAPE, CELLS, LEADS, PHOSPHORYLATION

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MLA
Szydzik, Joanna, et al. “ATR Inhibition Enables Complete Tumour Regression in ALK-Driven NB Mouse Models.” NATURE COMMUNICATIONS, vol. 12, no. 1, 2021, doi:10.1038/s41467-021-27057-2.
APA
Szydzik, J., Lind, D. E., Arefin, B., Kurhe, Y., Umapathy, G., Siaw, J. T., … Palmer, R. H. (2021). ATR inhibition enables complete tumour regression in ALK-driven NB mouse models. NATURE COMMUNICATIONS, 12(1). https://doi.org/10.1038/s41467-021-27057-2
Chicago author-date
Szydzik, Joanna, Dan E. Lind, Badrul Arefin, Yeshwant Kurhe, Ganesh Umapathy, Joachim Tetteh Siaw, Arne Claeys, et al. 2021. “ATR Inhibition Enables Complete Tumour Regression in ALK-Driven NB Mouse Models.” NATURE COMMUNICATIONS 12 (1). https://doi.org/10.1038/s41467-021-27057-2.
Chicago author-date (all authors)
Szydzik, Joanna, Dan E. Lind, Badrul Arefin, Yeshwant Kurhe, Ganesh Umapathy, Joachim Tetteh Siaw, Arne Claeys, Jonatan Gabre, Jimmy Van den Eynden, Bengt Hallberg, and Ruth H. Palmer. 2021. “ATR Inhibition Enables Complete Tumour Regression in ALK-Driven NB Mouse Models.” NATURE COMMUNICATIONS 12 (1). doi:10.1038/s41467-021-27057-2.
Vancouver
1.
Szydzik J, Lind DE, Arefin B, Kurhe Y, Umapathy G, Siaw JT, et al. ATR inhibition enables complete tumour regression in ALK-driven NB mouse models. NATURE COMMUNICATIONS. 2021;12(1).
IEEE
[1]
J. Szydzik et al., “ATR inhibition enables complete tumour regression in ALK-driven NB mouse models,” NATURE COMMUNICATIONS, vol. 12, no. 1, 2021.
@article{8727701,
  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.

Effective therapeutic options are still needed in neuroblastoma treatment. Here, the authors, through a comprehensive proteomics analysis, identify ATR as a potential therapeutic target of neuroblastoma and demonstrate the efficacy of the ATR inhibitor BAY1895344 in combination with the ALK tyrosine kinase inhibitor lorlatinib.}},
  articleno    = {{6813}},
  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 and Van den Eynden, Jimmy and Hallberg, Bengt and Palmer, Ruth H.}},
  issn         = {{2041-1723}},
  journal      = {{NATURE COMMUNICATIONS}},
  keywords     = {{General Physics and Astronomy,General Biochemistry,Genetics and Molecular Biology,General Chemistry,DEOXYCYTIDINE KINASE,GENE ATR,NEUROBLASTOMA,CANCER,REVEALS,CHECKPOINT,LANDSCAPE,CELLS,LEADS,PHOSPHORYLATION}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{18}},
  title        = {{ATR inhibition enables complete tumour regression in ALK-driven NB mouse models}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-27057-2}},
  volume       = {{12}},
  year         = {{2021}},
}

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