Preclinical assessment of combined BCL-2 and MCL-1 inhibition in high-risk neuroblastoma.
EJC Paediatric Oncology(2024)
摘要
Background
Neuroblastoma is the most common extracranial pediatric solid malignancy with high-risk patients showing survival rates less than 50%. These tumors frequently escape apoptosis through upregulation of the anti-apoptotic protein BCL-2. Unfortunately, monotherapy with the BCL-2 inhibitor venetoclax leads to therapy-induced resistance mediated by upregulation of MCL-1, thereby indicating that tumors could be responsive to dual inhibition of BCL-2 and MCL-1.
Methods
In vitro efficacy of venetoclax and multiple MCL-1 inhibitors (MIK665, S63845, AMG-176, AZD-5991) was studied in neuroblastoma cell lines with BCL-2 and/or MCL-1 dependency. Synergy assays were performed to identify the MCL-1 inhibitor with best performance in combination with venetoclax, followed by examining if dual BCL-2 and MCL-1 inhibition protects against resistance. Lastly, the combination was analyzed in two patient-derived xenograft (PDX) models.
Results
Venetoclax showed highest efficacy in neuroblastoma cell lines with high BCL-2 mRNA expression, BCL-2 protein levels or BIM:BCL-2 complex formation, while MCL-1 inhibitor efficacy was best correlated with BIM:MCL-1 complex levels. Most promising anti-tumor effects were observed following combination therapy with venetoclax and MIK665. Targeting BCL-2 and MCL-1 led to strong synergy and efficacy at low concentrations, induced apoptosis and prevented resistance. PDX validation studies combining venetoclax with MIK665 showed improved responses compared to monotherapies.
Conclusion
Dual inhibition of BCL-2 and MCL-1 in neuroblastoma cells showed highly efficacious and synergistic responses in vitro, but only led to mild additive effects in vivo. Hence, better understanding of in vivo efficacy and side effects of this combination treatment are warranted prior to clinical translation.
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关键词
Neuroblastoma,BCL-2,MCL-1,venetoclax,MIK665,combination therapy,pediatric cancer
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