High-throughput screening identifies idasanutlin as a resensitizing drug for venetoclax-resistant neuroblastoma cells

Lindy Vernooij, Laurel T. Bate-Eya, Lindy K. Alles, Jasmine Y. Lee, Bianca Koopmans, Hunter C. Jonus, Nil A. Schubert, Linda Schild, Daphne Lelieveld, David A. Egan, Mark Kerstjens, Ronald W. Stam, Jan Koster, Kelly C. Goldsmith, Jan J. Molenaar, M. M.Emmy Dolman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

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. Nonresistant 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.

Original languageEnglish
Pages (from-to)1161-1172
Number of pages12
JournalMolecular Cancer Therapeutics
Volume20
Issue number6
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
The research in this article was supported by grants from the Villa Joep Foundation (grant BCL-2 in neuroblastoma), the Kinderen Kankervrij Foundation (KiKa; grant 189), ERC-START (grant PREDICT-716079), NWO-Vidi (grant 91716482) and Aflac Pilot grant (to K.C. Goldsmith). We would like to thank Dr. C. Patrick Reynolds and Cogcell.org for providing us with the COG-N-424x PDX model and the CHOA Pediatric Biorepository for the CHOA-NBX-4 PDX model.

Publisher Copyright:
© 2021 American Association for Cancer Research.

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