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

Autor: Ruth H. Palmer, Joachim T. Siaw, Badrul Arefin, Yeshwant Kurhe, Jimmy Van den Eynden, Arne Claeys, Ganesh Umapathy, Bengt Hallberg, Jonatan L Gabre, Joanna Szydzik, Dan E. Lind
Rok vydání: 2021
Předmět:
DNA Repair
Cell
General Physics and Astronomy
Ataxia Telangiectasia Mutated Proteins
Proteomics
Mice
Neuroblastoma
0302 clinical medicine
GENE ATR
Antineoplastic Combined Chemotherapy Protocols
Medicine and Health Sciences
Anaplastic Lymphoma Kinase
RNA-Seq
PHOSPHORYLATION
0303 health sciences
Multidisciplinary
Chemistry
Phosphoproteomics
CANCER
3. Good health
medicine.anatomical_structure
Checkpoint signalling
LEADS
030220 oncology & carcinogenesis
Female
CHECKPOINT
Genetically modified mouse
DNA damage
Morpholines
Science
Genetics and Molecular Biology
DEOXYCYTIDINE KINASE
Article
General Biochemistry
Genetics and Molecular Biology
Paediatric cancer
03 medical and health sciences
Cell Line
Tumor
REVEALS
medicine
Animals
Humans
Protein Kinase Inhibitors
030304 developmental biology
LANDSCAPE
Cell growth
Growth factor signalling
General Chemistry
medicine.disease
Xenograft Model Antitumor Assays
Disease Models
Animal
General Biochemistry
NEUROBLASTOMA
CELLS
Cancer cell
Cancer research
Pyrazoles
DNA Damage
Zdroj: NATURE COMMUNICATIONS
Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021)
Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-021-27057-2
Popis: 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.
Databáze: OpenAIRE
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