1 型神经纤维瘤病 (NF1) 是一种由 NF1 基因突变引起的遗传性疾病，与各种症状相关，包括神经内良性肿瘤（称为神经纤维瘤）的形成。目前药物治疗有限。丝裂原激活蛋白激酶激酶 (MEK) 抑制剂司美替尼 (selumetinib) 用于治疗部分丛状神经纤维瘤 (PN)，但并不总是有效，并且可能引起副作用。因此，显然需要发现针对缺乏 NF1 的肿瘤细胞的新药。使用 NF1 果蝇细胞模型，我们进行了合成致死筛选，以确定新的药物靶点。我们鉴定了 54 个候选基因，并通过可变剂量分析作为二次筛选进行了验证。可以使用现有药物来靶向与五种候选药物相关的途径。其中，氯喹 (CQ) 和巴弗洛霉素 A1 已知以自噬途径为靶点，显示出选择性杀死 NF1 缺陷的果蝇细胞的最大潜力。当进一步研究自噬相关基因时，我们发现测试的 30 个基因中有 14 个与 NF1 存在合成致死相互作用。这 14 个基因涉及自噬途径的多个方面，并且可以用介导自噬途径的其他药物作为靶点，尽管 CQ 是最有效的。自噬抑制剂的致死作用在一组缺乏 NF1 的雪旺细胞系中得以保留，这凸显了它们的转化潜力。 CQ 的作用在果蝇 NF1 体内模型和小鼠体内生长的异种移植的 NF1 缺陷肿瘤细胞系中也得到保留，CQ 治疗比司美替尼治疗更显着地减少肿瘤生长。此外，CQ 和 Selumetinib 联合治疗导致 NF1 缺陷细胞活力进一步降低。总之，NF1 缺陷的细胞很容易受到自噬途径的破坏。该通路代表了治疗 NF1 相关肿瘤的一个有希望的靶标，我们确定 CQ 作为治疗 NF1 肿瘤的候选药物。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutation of the NF1 gene that is associated with various symptoms, including the formation of benign tumors, called neurofibromas, within nerves. Drug treatments are currently limited. The mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib is used for a subset of plexiform neurofibromas (PNs) but is not always effective and can cause side effects. Therefore, there is a clear need to discover new drugs to target NF1-deficient tumor cells. Using a Drosophila cell model of NF1, we performed synthetic lethal screens to identify novel drug targets. We identified 54 gene candidates, which were validated with variable dose analysis as a secondary screen. Pathways associated with five candidates could be targeted using existing drugs. Among these, chloroquine (CQ) and bafilomycin A1, known to target the autophagy pathway, showed the greatest potential for selectively killing NF1-deficient Drosophila cells. When further investigating autophagy-related genes, we found that 14 out of 30 genes tested had a synthetic lethal interaction with NF1. These 14 genes are involved in multiple aspects of the autophagy pathway and can be targeted with additional drugs that mediate the autophagy pathway, although CQ was the most effective. The lethal effect of autophagy inhibitors was conserved in a panel of human NF1-deficient Schwann cell lines, highlighting their translational potential. The effect of CQ was also conserved in a Drosophila NF1 in vivo model and in a xenografted NF1-deficient tumor cell line grown in mice, with CQ treatment resulting in a more significant reduction in tumor growth than selumetinib treatment. Furthermore, combined treatment with CQ and selumetinib resulted in a further reduction in NF1-deficient cell viability. In conclusion, NF1-deficient cells are vulnerable to disruption of the autophagy pathway. This pathway represents a promising target for the treatment of NF1-associated tumors, and we identified CQ as a candidate drug for the treatment of NF1 tumors.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.