Neuroblastoma is the leading cause of cancer death in children aged 1 to 4 years. Particularly, five-year overall survival for high-risk neuroblastoma is below 50% with no curative options when refractory or relapsed. Most of current therapies target cell division and proliferation, thereby inducing DNA damage and programmed cell death. However, aggressive tumours often present alterations of these processes and are resistant to therapy. Therefore, exploring alternative pathways to induce tumour cell death will provide new therapeutic opportunities for these patients. In this study we aimed at testing the therapeutic potential of ABTL0812, a novel anticancer drug that induces cytotoxic autophagy to eliminate cancer cells, which is currently in phase II clinical trials of adult tumours. Here, we show that ABTL0812 impaired the viability of clinical representative neuroblastoma cell lines regardless of genetic alterations associated to bad prognosis and resistance to therapy. Oral administration of ABTL0812 to mice bearing neuroblastoma xenografts impaired tumour growth. Furthermore, our findings revealed that, in neuroblastoma, ABTL0812 induced cancer cell death via induction of endoplasmic reticulum stress, activation of the unfolded protein response, autophagy and apoptosis. Remarkably, ABTL0812 potentiated the antitumour activity of chemotherapies and differentiating agents such as irinotecan and 13-cis-retinoic acid. In conclusion, ABTL0812 distinctive mechanism of action makes it standout to be used alone or in combination in high-risk neuroblastoma patients.

神经母细胞瘤是 1 至 4 岁儿童癌症死亡的主要原因。特别是，高危神经母细胞瘤的五年总生存率低于 50%，在难治或复发时没有治愈选择。目前的大多数疗法都针对细胞分裂和增殖，从而诱导 DNA 损伤和程序性细胞死亡。然而，侵袭性肿瘤经常表现出这些过程的改变并且对治疗具有抗性。因此，探索诱导肿瘤细胞死亡的替代途径将为这些患者提供新的治疗机会。在这项研究中，我们旨在测试 ABTL0812 的治疗潜力，ABTL0812 是一种新型抗癌药物，可诱导细胞毒性自噬以消除癌细胞，目前正处于成人肿瘤的 II 期临床试验中。这里，我们表明 ABTL0812 损害了临床代表性神经母细胞瘤细胞系的活力，而不管与不良预后和治疗抵抗相关的遗传改变如何。向携带神经母细胞瘤异种移植物的小鼠口服 ABTL0812 会损害肿瘤生长。此外，我们的研究结果表明，在神经母细胞瘤中，ABTL0812 通过诱导内质网应激、未折叠蛋白反应的激活、自噬和细胞凋亡来诱导癌细胞死亡。值得注意的是，ABTL0812 增强了化疗和分化剂（如伊立替康和 13 我们的研究结果表明，在神经母细胞瘤中，ABTL0812 通过诱导内质网应激、未折叠蛋白反应的激活、自噬和细胞凋亡来诱导癌细胞死亡。值得注意的是，ABTL0812 增强了化疗和分化剂（如伊立替康和 13 我们的研究结果表明，在神经母细胞瘤中，ABTL0812 通过诱导内质网应激、未折叠蛋白反应的激活、自噬和细胞凋亡来诱导癌细胞死亡。值得注意的是，ABTL0812 增强了化疗和分化剂（如伊立替康和 13-顺式-视黄酸。总之，ABTL0812独特的作用机制使其在高危神经母细胞瘤患者中单独或联合使用时脱颖而出。