Stevens Megan, Wang Yuanli, Bouley Stephanie J, Mandigo Torrey R, Sharma Aditi, Sengupta Sonali, Housden Amy, Perrimon Norbert, Walker James A, Housden Benjamin E
Living Systems Institute, University of Exeter, UK.
Department of Clinical and Biomedical Science, University of Exeter, UK.
Mol Oncol. 2025 Mar;19(3):825-851. doi: 10.1002/1878-0261.13704. Epub 2024 Aug 11.
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.
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，与多种症状相关，包括在神经内形成称为神经纤维瘤的良性肿瘤。目前药物治疗有限。丝裂原活化蛋白激酶激酶（MEK）抑制剂司美替尼用于一部分丛状神经纤维瘤（PNs），但并非总是有效，且会引起副作用。因此，显然需要发现针对NF1缺陷肿瘤细胞的新药。我们使用NF1的果蝇细胞模型进行了合成致死筛选，以鉴定新的药物靶点。我们鉴定出54个基因候选物，并通过可变剂量分析作为二次筛选进行了验证。与五个候选物相关的通路可以使用现有药物进行靶向。其中，已知靶向自噬通路的氯喹（CQ）和巴弗洛霉素A1显示出选择性杀死NF1缺陷果蝇细胞的最大潜力。在进一步研究自噬相关基因时，我们发现所测试的30个基因中有14个与NF1存在合成致死相互作用。这14个基因参与自噬通路的多个方面，并且可以用介导自噬通路的其他药物进行靶向，尽管CQ是最有效的。自噬抑制剂的致死作用在一组人类NF1缺陷雪旺细胞系中是保守的，突出了它们的转化潜力。CQ的作用在果蝇NF1体内模型和在小鼠体内生长的异种移植NF1缺陷肿瘤细胞系中也是保守的，CQ治疗导致肿瘤生长的减少比司美替尼治疗更显著。此外，CQ和司美替尼联合治疗导致NF1缺陷细胞活力进一步降低。总之，NF1缺陷细胞易受自噬通路破坏的影响。该通路是治疗NF1相关肿瘤的一个有前景的靶点，并且我们鉴定出CQ作为治疗NF1肿瘤的候选药物。
