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

Author

Listed:
  • 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
    Ghent University)

  • Jimmy Eynden

    (Ghent University)

  • Bengt Hallberg

    (University of Gothenburg)

  • Ruth H. Palmer

    (University of Gothenburg)

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.

Suggested Citation

  • Joanna Szydzik & Dan E. Lind & Badrul Arefin & Yeshwant Kurhe & Ganesh Umapathy & Joachim Tetteh Siaw & Arne Claeys & Jonatan L. Gabre & Jimmy Eynden & Bengt Hallberg & Ruth H. Palmer, 2021. "ATR inhibition enables complete tumour regression in ALK-driven NB mouse models," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27057-2
    DOI: 10.1038/s41467-021-27057-2
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