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Published on: December 7, 2014
High-Throughput Screening Identifies Idasanutlin as a Resensitizing Drug for Venetoclax-Resistant Neuroblastoma Cells
Lindy Vernooij1, Laurel T Bate-Eya1, Lindy K Alles1
1Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Abstract:
Neuroblastoma tumors frequently overexpress the anti-apoptotic protein B-cell lymphoma/leukemia 2 (BCL-2). We previously showed that treating BCL-2-dependent neuroblastoma cells with the BCL-2 inhibitor venetoclax results in apoptosis, but unfortunately partial therapy resistance is observed. The current study describes the identification of drugs capable of resensitizing venetoclax-resistant neuroblastoma cells to venetoclax. To examine these effects, venetoclax resistance was induced in BCL-2-dependent neuroblastoma cell lines KCNR and SJNB12 by continuous exposure to high venetoclax concentrations. Non-resistant and venetoclax-resistant neuroblastoma cell lines were exposed to a 209-compound library in the absence and presence of venetoclax to identify compounds that were more effective in the venetoclax-resistant cell lines under venetoclax pressure. Top hits were further validated in combination with venetoclax using BCL-2-dependent neuroblastoma model systems. Overall, high-throughput drug screening identified the MDM2 inhibitor idasanutlin as a promising resensitizing agent for venetoclax-resistant neuroblastoma cell lines. Idasanutlin treatment induced BAX-mediated apoptosis in venetoclax-resistant neuroblastoma cells in the presence of venetoclax, whereas it caused p21-mediated growth arrest in control cells. In vivo combination treatment showed tumor regression and superior efficacy over single-agent therapies in a BCL-2-dependent neuroblastoma cell line xenograft and a patient-derived xenograft. However, xenografts less dependent on BCL-2 were not sensitive to venetoclax-idasanutlin combination therapy. This study demonstrates that idasanutlin can overcome resistance to the BCL-2 inhibitor venetoclax in preclinical neuroblastoma model systems, which supports clinical development of a treatment strategy combining the two therapies.
Insights
This study found that idasanutlin can resensitize venetoclax-resistant neuroblastoma cells. Combining idasanutlin with venetoclax shows promise for treating neuroblastoma by overcoming therapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Neuroblastoma tumors often overexpress B-cell lymphoma/leukemia 2 (BCL-2), an anti-apoptotic protein.
- While BCL-2 inhibitors like venetoclax induce apoptosis in neuroblastoma, partial therapy resistance is a significant clinical challenge.
Purpose of the Study:
- To identify drugs that can resensitize venetoclax-resistant neuroblastoma cells to venetoclax.
- To evaluate the efficacy of combining venetoclax with identified resensitizing agents in preclinical neuroblastoma models.
Main Methods:
- Venetoclax resistance was induced in neuroblastoma cell lines (KCNR, SJNB12).
- A 209-compound library screen was performed on resistant and non-resistant cells with and without venetoclax.
- Top drug candidates were validated in combination with venetoclax using cell lines and xenograft models.
Main Results:
- High-throughput screening identified the MDM2 inhibitor idasanutlin as a potent resensitizing agent.
- Idasanutlin induced BAX-mediated apoptosis in venetoclax-resistant cells when combined with venetoclax.
- Combination therapy demonstrated tumor regression and superior efficacy in BCL-2-dependent xenografts but not in less BCL-2-dependent models.
Conclusions:
- Idasanutlin effectively overcomes venetoclax resistance in preclinical neuroblastoma models.
- The combination of venetoclax and idasanutlin shows potential for clinical development in BCL-2-dependent neuroblastoma.
