抑制自噬是治疗 1 型神经纤维瘤病肿瘤的一种新方法。

IF 6.6 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Megan Stevens, Yuanli Wang, Stephanie J Bouley, Torrey R Mandigo, Aditi Sharma, Sonali Sengupta, Amy Housden, Norbert Perrimon, James A Walker, Benjamin E Housden
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引用次数: 0

摘要

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,与各种症状有关,包括在神经内形成良性肿瘤(称为神经纤维瘤)。目前药物治疗效果有限。丝裂原活化蛋白激酶激酶(MEK)抑制剂赛鲁米替尼(selumetinib)可用于丛状神经纤维瘤(PNs)的治疗,但并不总是有效,而且会产生副作用。因此,显然有必要发现针对NF1缺陷肿瘤细胞的新药。我们利用果蝇的 NF1 细胞模型进行了合成致死筛选,以确定新的药物靶点。我们确定了 54 个候选基因,并通过变剂量分析进行了二次筛选验证。与五个候选基因相关的通路可以使用现有药物作为靶点。其中,氯喹(CQ)和巴非罗霉素 A1(已知以自噬途径为靶点)在选择性杀死 NF1 缺陷果蝇细胞方面表现出最大的潜力。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 个基因涉及自噬途径的多个方面,可以用其他介导自噬途径的药物作为靶点,但 CQ 是最有效的。自噬抑制剂的致死效应在一组人类 NF1 缺陷许旺细胞系中是一致的,这突显了它们的转化潜力。CQ在果蝇NF1体内模型和在小鼠体内生长的异种移植NF1缺陷肿瘤细胞系中的效果也是一致的,CQ治疗比塞鲁替尼治疗能更显著地减少肿瘤生长。此外,CQ 和塞鲁替尼联合治疗可进一步降低 NF1 基因缺陷细胞的存活率。总之,NF1缺陷细胞易受自噬途径破坏的影响。这一途径是治疗NF1相关肿瘤的一个很有前景的靶点,我们将CQ确定为治疗NF1肿瘤的候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of autophagy as a novel treatment for neurofibromatosis type 1 tumors.

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.

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来源期刊
Molecular Oncology
Molecular Oncology Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
11.80
自引率
1.50%
发文量
203
审稿时长
10 weeks
期刊介绍: Molecular Oncology highlights new discoveries, approaches, and technical developments, in basic, clinical and discovery-driven translational cancer research. It publishes research articles, reviews (by invitation only), and timely science policy articles. The journal is now fully Open Access with all articles published over the past 10 years freely available.
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