Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germlineNF1gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at theNF1locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose–response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy.Methods: Using concentration–response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line,S= log[EFF/AC50], and (b) a relative score,ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line.ΔSwas applied to data from high-throughput screening (HTS) of a drug panel tested onNF1−/−tumor cells, using immortalized non-tumorNF1+/−cells as a reference.Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. TheΔStechnique used here, in tandem with a supplementalΔSweb tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.
背景：1型神经纤维瘤病（NF1）是一种遗传性疾病，其特征为杂合性胚系NF1基因突变，使患者易发生丛状神经纤维瘤。这类肿瘤虽属良性，但常导致外周神经鞘变形，由NF1位点杂合性缺失诱发，并可进展为恶性外周神经鞘肿瘤（MPNST）。目前尚无获批药物治疗成人NF1相关不可切除丛状神经纤维瘤，仅有一种药物（司美替尼）获FDA批准用于治疗有症状的儿童丛状神经纤维瘤，这凸显了进一步药物筛选与开发的必要性。在高通量筛选中，通常通过测量体外效价（AC50）或曲线下面积（AUC）来评估药物对细胞系的作用效果。然而，不同药物与细胞系的剂量反应曲线存在差异，且部分有效现象频发，表明仅凭这些指标难以全面反映整体疗效。 方法：基于浓度反应数据，我们将反应有效性（EFF）与效价（AC50）整合为：（a）表征化合物对单个细胞系作用的评分S= log[EFF/AC50]；（b）表征参照细胞系（如非肿瘤细胞）与测试细胞系（肿瘤细胞）间相对差异的评分ΔS。将ΔS应用于NF1−/−肿瘤细胞药物组合的高通量筛选数据，并以永生化非肿瘤NF1+/−细胞作为参照。 结果：我们筛选出对MAPK-ERK、PI3K-AKT通路及5-羟色胺相关靶点等预期通路具有敏感性的靶向药物。本研究采用的ΔS技术结合配套的ΔS网络工具，简化了高通量筛选分析流程，可能为深入研究NF1相关癌症的药物反应提供新起点。该工具也有望应用于多种其他癌症的药物研发。
肿瘤(癌症)患者之家