Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN-amplified high-risk neuroblastoma

Kamili, A.; Hearn, B. A.; Temelkoska, I.; Solomon, J.; Wheatley, M. S.; Bui, C. H. T.; Atkinson, C. J.; Elhassadi, L.-J.; Qureshi, S.; Murray, J.; Cadiz, R.; Gifford, A. J.; Cui, L.; Crowley, L.; Lin, A.; Mayoh, C.; Wong-Erasmus, M.; Failes, T. W.; Arndt, G. M.; Haber, M.; Norris, M. D.; Dolman, M. E. M.; Trahair, T. N.; Fletcher, J. I.

doi:10.64898/2026.09.06.749004

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bioRxiv · 10.64898/2026.09.06.749004

Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN-amplified high-risk neuroblastoma

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Abstract

Purpose: Treatment for children with high-risk neuroblastoma relies on conventional chemotherapy and anti-GD2 immunotherapy. However, 5-year survival is only 50%, with high rates of late effects. Targeted therapy combinations are a major priority for these patients. The BCL2 inhibitor venetoclax, in combination with cyclophosphamide/topotecan, has clinical activity in relapsed and refractory neuroblastoma. We sought more effective and safer venetoclax combinations through systematic preclinical testing. Experimental design: Synergistic combinations were identified by high-throughput screening using patient-derived xenograft (PDX) models and confirmed in vivo. The leading combination (venetoclax-alisertib) was compared to combination chemotherapy in a clinical trial-like study using 22 PDX models, in scheduling experiments designed to reduce short-term toxicity, and in combination with anti-GD2 immunotherapy. BCL2 and Bim-BCL2 complex protein levels were assessed as predictors of sensitivity. Results: In vitro synergy with venetoclax was observed for standard-of-care chemotherapies and targeted agents, including DNA topoisomerase, microtubule, HDAC and Aurora kinase A (AURKA) inhibitors. Venetoclax-alisertib was particularly effective in vivo. In an n=1 study, venetoclax-alisertib induced objective response in all models. Activity was most striking in models of MYCN-amplified disease (n=12), doubling median survival time compared to cyclophosphamide/topotecan, and outperforming venetoclax-cyclophosphamide-topotecan. Efficacy was maintained with discontinuous schedules, minimizing hematological toxicity without substantially compromising activity. PDX-engrafted animals treated with venetoclax-alisertib and anti-GD2 immunotherapy survived tumor-free long-term. BCL2 expression and BCL2-Bim complex levels were of limited value for predicting response. Conclusion: Our findings support advancement of BCL2-AURKA inhibition to clinical trial for neuroblastoma with or without anti-GD2 immunotherapy, particularly in patients with MYCN amplified disease.

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Kamili, A., Hearn, B. A., Temelkoska, I., Solomon, J., Wheatley, M. S., Bui, C. H. T., Atkinson, C. J., Elhassadi, L.-J., Qureshi, S., Murray, J., Cadiz, R., Gifford, A. J., Cui, L., Crowley, L., Lin, A., Mayoh, C., Wong-Erasmus, M., Failes, T. W., Arndt, G. M., Haber, M., Norris, M. D., Dolman, M. E. M., Trahair, T. N., Fletcher, J. I.. 2026-09-10. Preclinical trial supports dual inhibition of BCL2 and Aurora kinase A for MYCN-amplified high-risk neuroblastoma. https://doi.org/10.64898/2026.09.06.749004

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