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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase / antagonists & inhibitors
  • Anaplastic Lymphoma Kinase / genetics
  • Anaplastic Lymphoma Kinase / metabolism
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Line, Tumor
  • DNA Damage
  • DNA Repair
  • Disease Models, Animal
  • Female
  • Humans
  • Mice
  • Morpholines / pharmacology
  • Morpholines / therapeutic use
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / genetics
  • Neuroblastoma / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • RNA-Seq
  • Xenograft Model Antitumor Assays


  • BAY 1895344
  • Morpholines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Atr protein, mouse
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins