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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
ATR inhibition enables complete tumour regression in ALK-driven NB mouse models
Joanna Szydzik1, Dan E Lind1, Badrul Arefin1
1Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-40530, Gothenburg, Sweden.
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.
Insights
Targeting ATR in neuroblastoma (NB) shows promise. Inhibiting ATR, a key player in DNA damage response, significantly reduced NB cell growth and led to complete tumor regression in mouse models, suggesting a new therapeutic avenue for high-risk patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- High-risk neuroblastoma (NB) is challenging to treat, often driven by MYCN amplification and ALK mutations.
- Oncogenes like MYCN and ALK induce replication stress, creating therapeutic vulnerabilities.
- Current treatment options for high-risk NB are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of ATR activity in ALK-driven neuroblastoma.
- To evaluate the efficacy of the ATR inhibitor BAY1895344 in neuroblastoma models.
- To characterize the molecular responses of neuroblastoma cells and tumors to ATR inhibition.
Main Methods:
- Phosphoproteomic analysis to identify ATR activity in NB cells.
- Treatment of NB cells and mouse models with the ATR inhibitor BAY1895344.
- RNA-Seq, proteomics, and phosphoproteomics to analyze cellular and tumor responses.
- Combination therapy studies with ATR and ALK inhibitors in mouse models.
Main Results:
- Phosphoproteomic analysis revealed significant ATR activity in ALK-driven NB cells.
- BAY1895344 potently inhibited NB cell growth and proliferation.
- ATR inhibition modulated key DNA damage response pathways in NB cells.
- Combined ATR and ALK inhibition resulted in complete tumor regression in mouse models.
Conclusions:
- ATR inhibition is a promising therapeutic strategy for neuroblastoma, particularly high-risk subtypes.
- Targeting oncogene-induced replication stress via ATR inhibition offers a viable treatment approach.
- Combined ATR and ALK inhibition demonstrates potent anti-tumor activity and warrants further clinical investigation.
