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ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

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Abstract
High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and Anaplastic Lymphoma Kinase (ALK), which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR (ataxia telangiectasia and Rad3-related)/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-d ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-d combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.
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MLA
Borenäs, Marcus, et al. “ALK Signaling Primes the DNA Damage Response Sensitizing ALK-Driven Neuroblastoma to Therapeutic ATR Inhibition.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 121, no. 1, Proceedings of the National Academy of Sciences, 2024, doi:10.1073/pnas.2315242121.
APA
Borenäs, M., Umapathy, G., Lind, D. E., Lai, W.-Y., Guan, J., Johansson, J., … Palmer, R. H. (2024). ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 121(1). https://doi.org/10.1073/pnas.2315242121
Chicago author-date
Borenäs, Marcus, Ganesh Umapathy, Dan E. Lind, Wei-Yun Lai, Jikui Guan, Joel Johansson, Eva Jennische, et al. 2024. “ALK Signaling Primes the DNA Damage Response Sensitizing ALK-Driven Neuroblastoma to Therapeutic ATR Inhibition.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 121 (1). https://doi.org/10.1073/pnas.2315242121.
Chicago author-date (all authors)
Borenäs, Marcus, Ganesh Umapathy, Dan E. Lind, Wei-Yun Lai, Jikui Guan, Joel Johansson, Eva Jennische, Alexander Schmidt, Yeshwant Kurhe, Jonatan Linus Gabre, Agata Aniszewska, Anneli Strömberg, Mats Bemark, Michael N. Hall, Jimmy Van den Eynden, Bengt Hallberg, and Ruth H. Palmer. 2024. “ALK Signaling Primes the DNA Damage Response Sensitizing ALK-Driven Neuroblastoma to Therapeutic ATR Inhibition.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 121 (1). doi:10.1073/pnas.2315242121.
Vancouver
1.
Borenäs M, Umapathy G, Lind DE, Lai W-Y, Guan J, Johansson J, et al. ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2024;121(1).
IEEE
[1]
M. Borenäs et al., “ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition,” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 121, no. 1, 2024.
@article{01HKX41V1RT27BSY6S4BJ5KTWJ,
  abstract     = {{High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and Anaplastic Lymphoma Kinase (ALK), which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR (ataxia telangiectasia and Rad3-related)/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-d ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-d combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.}},
  articleno    = {{e2315242121}},
  author       = {{Borenäs, Marcus and Umapathy, Ganesh and Lind, Dan E. and Lai, Wei-Yun and Guan, Jikui and Johansson, Joel and Jennische, Eva and Schmidt, Alexander and Kurhe, Yeshwant and Gabre, Jonatan Linus and Aniszewska, Agata and Strömberg, Anneli and Bemark, Mats and Hall, Michael N. and Van den Eynden, Jimmy and Hallberg, Bengt and Palmer, Ruth H.}},
  issn         = {{0027-8424}},
  journal      = {{PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}},
  keywords     = {{Multidisciplinary}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{12}},
  publisher    = {{Proceedings of the National Academy of Sciences}},
  title        = {{ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition}},
  url          = {{http://doi.org/10.1073/pnas.2315242121}},
  volume       = {{121}},
  year         = {{2024}},
}

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