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Szydzik J, Lind DE, Arefin B, et al. ATR inhibition enables complete tumour regression in ALK-driven NB mouse models. Nat Commun. 2021;12(1):6813doi: 10.1038/s41467-021-27057-2.
Szydzik, J., Lind, D. E., Arefin, B., Kurhe, Y., Umapathy, G., Siaw, J. T., Claeys, A., Gabre, J. L., Van den Eynden, J., Hallberg, B., & Palmer, R. H. (2021). ATR inhibition enables complete tumour regression in ALK-driven NB mouse models. Nature communications, 12(1), 6813. https://doi.org/10.1038/s41467-021-27057-2
Szydzik, Joanna, et al. "ATR inhibition enables complete tumour regression in ALK-driven NB mouse models." Nature communications vol. 12,1 (2021): 6813. doi: https://doi.org/10.1038/s41467-021-27057-2
Szydzik J, Lind DE, Arefin B, Kurhe Y, Umapathy G, Siaw JT, Claeys A, Gabre JL, Van den Eynden J, Hallberg B, Palmer RH. ATR inhibition enables complete tumour regression in ALK-driven NB mouse models. Nat Commun. 2021 Nov 24;12(1):6813. doi: 10.1038/s41467-021-27057-2. PMID: 34819497; PMCID: PMC8613282.
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Nat Commun. 2021 Nov 24;12(1):6813. doi: 10.1038/s41467-021-27057-2.

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

Nature communications

Joanna Szydzik, Dan E Lind, Badrul Arefin, Yeshwant Kurhe, Ganesh Umapathy, Joachim Tetteh Siaw, Arne Claeys, Jonatan L Gabre, Jimmy Van den Eynden, Bengt Hallberg, Ruth H Palmer

Affiliations

  1. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden.
  2. Department of Human Structure and Repair, Anatomy and Embryology Unit, Ghent University, 9000, Ghent, Belgium.
  3. Department of Human Structure and Repair, Anatomy and Embryology Unit, Ghent University, 9000, Ghent, Belgium. [email protected].
  4. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden. [email protected].
  5. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden. [email protected].

PMID: 34819497 PMCID: PMC8613282 DOI: 10.1038/s41467-021-27057-2

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.

© 2021. The Author(s).

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