目的:Selumetinib是FDA批准的针对1型神经纤维瘤病(NF1)的丛状神经纤维瘤的靶向治疗方法,在大多数患者中,但不是所有的病人。在这个概念验证研究中,我们展示了单细胞RNA测序(scRNAseq)作为在单细胞水平定量司美替尼药物应答的技术.
方法:来自神经纤维瘤活检的scRNAseq数据来自公共基因组学存储库。通过标准聚类技术鉴定雪旺氏细胞群,并基于来自BeyondCell敏感性文库的500个基因的司美替尼敏感性标签的表达模式,以0(抗性)至1(敏感性)的等级定量单细胞司美替尼敏感性。
结果:我们的最终分析中包括了总共7个丛状神经纤维瘤。样品中施万细胞的中位数绝对数量为658个细胞(IQR:1,029个细胞,Q1-Q3:135个细胞至1,163个细胞)。不同样本的司米替尼敏感性谱存在统计学上的显著差异(p<0.001)。具有最高中位司美替尼敏感性评分的肿瘤的中位司美替尼敏感性评分为0.64(IQR:0.14,Q1-Q3:0.59-0.70,n=112个细胞),而具有最低中位司美替尼敏感性评分的肿瘤的中位值为0.37(IQR:0.21,Q1-Q3:0.27-0.48,n=1,034个细胞)。
结论:scRNAseq的丛状神经纤维瘤活检显示了在单细胞水平上对司美替尼的不同敏感性。这些发现可能解释了司美替尼用于NF1的临床试验中的部分反应,并证明了收集scRNAseq数据用于未来NF1试验的价值。
OBJECTIVE: Selumetinib is an FDA-approved targeted therapy for plexiform neurofibromas in neurofibromatosis type 1(NF1) with durable response rates seen in most, but not all patients. In this proof-of-concept study, we demonstrate single-cell RNA sequencing(scRNAseq) as a technique for quantifying drug response to selumetinib at the single cell level.
METHODS: scRNAseq data from neurofibroma biopsies was obtained from a public genomics repository. Schwann cell populations were identified through standard clustering techniques and single-cell selumetinib sensitivity was quantified on a scale of 0(resistant) to 1(sensitive) based on the expression pattern of a 500 gene selumetinib sensitivity signature from the BeyondCell sensitivity library.
RESULTS: A total of seven plexiform neurofibromas were included in our final analysis. The median absolute number of Schwann cells across samples was 658 cells (IQR: 1,029 cells, Q1-Q3: 135 cells to 1,163 cells). There was a statistically significant difference in selumetinib sensitivity profiles across samples (p < 0.001). The tumor with the highest median selumetinib sensitivity score had a median selumetinib sensitivity score of 0.64(IQR: 0.14, Q1-Q3: 0.59-0.70, n = 112 cells) and the tumor with the lowest median selumetinib sensitivity score had a median score of 0.37 (IQR: 0.21, Q1-Q3: 0.27-0.48, n = 1,034 cells).
CONCLUSIONS: scRNAseq of plexiform neurofibroma biopsies reveals differential susceptibilities to selumetinib on a single cell level. These findings may explain the partial responses seen in clinical trials of selumetinib for NF1 and demonstrate the value of collecting scRNAseq data for future NF1 trials.