ALK/ATR combination therapy is effective in neuroblastoma mouse tumors driven by MYCN

Borenas, M.; Lind, D. E.; Lehnberg, A.; Zentenius, E.; Esselius, M.; Jennische, E.; Leverson, J.; Guan, J.; Aniszewska, A.; Van den Eynden, J.; Hallberg, B.; Palmer, R.

doi:10.1101/2025.07.17.665300

bioRxiv · 10.1101/2025.07.17.665300

ALK/ATR combination therapy is effective in neuroblastoma mouse tumors driven by MYCN

Borenas, M.·Lind, D. E.·Lehnberg, A.·Zentenius, E.·Esselius, M.·Jennische, E.·Leverson, J.·Guan, J.·Aniszewska, A.·Van den Eynden, J.·Hallberg, B.·Palmer, R.

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Abstract

Summary paragraphOne of the key features of high-risk neuroblastoma (NB) is MYCN-amplification. While MYCN is still regarded as therapeutically challenging despite intensive efforts to find targeting compounds, inhibitors against Anaplastic Lymphoma Kinase (ALK) are now being evaluated among ALK-driven NB patients with promising results. There is a pressing need to find alternative treatment regimens for ALK naive MYCN-amplified patients, as current regimes are accompanied by significant mortality and morbidity. Here we show that genetically removing Alk in the Th-MYCN-driven engineered NB mouse model (GEMM) resulted in decreased tumor penetrance, and survival of Th-MYCN homozygote GEMMs, suggesting that Alk activity contributes to aggressiv e neuroblastoma development in this model. Given the high levels of replication stress induced in Th-MYCN tumors, we employed inhibitors of Ataxia Telangiectasia Rad3 related (ATR), combining ATR and ALK inhibition in a 14-day treatment regime, and comparing with ATR inhibitor monotreatment. Th-MYCN tumor bearing mice that received ATRi/ALKi combination treatment exhibited significantly increased survival compared to ATRi alone, that was sustained over time. Together, our data highlight a potentially effective treatment option for the currently challenging category of MYCN-amplified NB patients lacking ALK mutations.

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Borenas, M., Lind, D. E., Lehnberg, A., Zentenius, E., Esselius, M., Jennische, E., Leverson, J., Guan, J., Aniszewska, A., Van den Eynden, J., Hallberg, B., Palmer, R.. 2025-07-21. ALK/ATR combination therapy is effective in neuroblastoma mouse tumors driven by MYCN. https://doi.org/10.1101/2025.07.17.665300

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