神经母细胞瘤是一种儿科癌症，其以化疗耐药性导致预后不良为特征，凸显了对更好治疗选择的需求。在这里，我们询问了BH3类似物抑制BCL2蛋白是否可以消除化疗耐药的神经母细胞瘤细胞。我们利用顺铂耐药的神经母细胞瘤细胞系以及复发前后的患者组织，研究了化疗耐药后BCL2蛋白的变化。在直接比较顺铂耐药细胞的过程中，我们发现对BCL2/BCL-XL抑制剂的敏感性明显降低，这与MCL1依赖性的增加和患者肿瘤组织中MCL1的高表达相关。在化疗耐药细胞中筛选FDA批准的抗癌药物，发现其中一些药物可能与临床测试的BH3类似物ABT263联合使用具有益处，但选择性MCL1抑制剂S63845无协同药物相互作用。对化疗耐药神经母细胞瘤的潜在治疗选择进行进一步研究，发现基于NK细胞的免疫治疗非常有前景，因为NK细胞能够有效杀死原始细胞和化疗耐药细胞。这些数据表明，BH3类似物的应用可能在一线治疗和复发疾病中有所不同。将基于NK细胞的免疫治疗与BH3类似物联合使用，可能进一步增加对化疗耐药神经母细胞瘤的杀伤作用，为复发神经母细胞瘤提供了新的治疗策略。©2023年。作者。

Neuroblastoma is a paediatric cancer that is characterised by poor prognosis for chemoresistant disease, highlighting the need for better treatment options. Here, we asked whether BH3-mimetics inhibiting BCL2 proteins may eliminate chemoresistant neuroblastoma cells.We utilised cisplatin-adapted neuroblastoma cell lines as well as patient tissues before and after relapse to study alterations of BCL2 proteins upon chemoresistance.In a direct comparison of cisplatin-resistant cells we identified a prominent loss of sensitivity to BCL2/BCL-XL inhibitors that is associated with an increase in MCL1 dependency and high expression of MCL1 in patient tumour tissues. Screening of FDA-approved anti-cancer drugs in chemoresistant cells identified therapeutics that may be beneficial in combination with the clinically tested BH3-mimetic ABT263, but no synergistic drug interactions with the selective MCL1 inhibitor S63845. Further exploration of potential treatment options for chemoresistant neuroblastoma identified immunotherapy based on NK cells as highly promising, since NK cells are able to efficiently kill both parental and chemoresistant cells.These data highlight that the application of BH3-mimetics may differ between first line treatment and relapsed disease. Combination of NK cell-based immunotherapy with BH3-mimetics may further increase killing of chemoresistant neuroblastoma, outlining a new treatment strategy for relapsed neuroblastoma.© 2023. The Author(s).