AI Article Synopsis
- High-risk neuroblastoma (NB) is associated with MYCN amplification and ALK mutations, making treatment challenging and highlighting the need for new therapies.
- Oncogenes like MYCN and ALK increase replication stress in cancer cells, which can be targeted for treatment; researchers identified the ATR inhibitor BAY1895344 as effective in inhibiting NB cell growth.
- Combining ATR and ALK inhibitors over two weeks leads to complete tumor regression in mouse models, indicating that ATR inhibition could significantly benefit high-risk NB patients experiencing oncogene-induced replication stress.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613282 | PMC |
| http://dx.doi.org/10.1038/s41467-021-27057-2 | DOI Listing |
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