School of Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, China.
Department of Oncology, General Hospital of Northern Theater Command, Shenyang, China.
J Gene Med. 2024 Jan;26(1):e3658. doi: 10.1002/jgm.3658.
Aberrant activation of the phosphatidlinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway has been shown to play an important role in lung adenocarcinoma (LUAD). The effect of KRAS mutations, one of the important signatures of LUAD, on the PI3K/AKT/mTOR pathway in LUAD remains unclear.
The Seurat package and principal component analysis were used for cell categorization of single-cell RNA sequencing data of LUAD. The AUCell score was used to assess the activity of the PI3K/AKT/mTOR pathway. Meanwhile, using the gene expression profiles and mutation profiles in the The Cancer Genome Atlas dataset, LUAD patients were categorized into KRAS-mutant (KRAS-MT) and KRAS-wild-types (KRAS-WT), and the corresponding enrichment scores were calculated using gene set enrichment analysis analysis. Finally, the subpopulation of cells with the highest pathway activity was identified, the copy number variation profile of this subpopulation was inscribed using the inferCNV package and the CMap database was utilized to make predictions for drugs targeting this subpopulation.
There is higher PI3K/AKT/mTOR pathway activity in LUAD epithelial cells with KRAS mutations, and high expression of KRAS, PIK3CA, AKT1 and PDPK1. In particular, we found significantly higher levels of pathway activity and associated gene expression in KRAS-MT than in KRAS-WT. We identified the highest pathway activity on a subpopulation of GRB2 epithelial cells and the presence of amplified genes within its pathway. Finally, drugs were able to target GRB2 epithelial cell subpopulations, such as wortmannin, palbociclib and angiogenesis inhibitor.
The present study provides a basic theory for the activation of the PI3K/AKT/mTOR signaling pathway as a result of KRAS mutations.
已证实磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的异常激活在肺腺癌（LUAD）中发挥着重要作用。LUAD 的重要特征之一 KRAS 突变对 LUAD 中 PI3K/AKT/mTOR 通路的影响尚不清楚。
使用 Seurat 包和主成分分析对 LUAD 的单细胞 RNA 测序数据进行细胞分类。使用 AUCell 评分评估 PI3K/AKT/mTOR 通路的活性。同时，使用 The Cancer Genome Atlas 数据集的基因表达谱和突变谱，将 LUAD 患者分为 KRAS 突变型（KRAS-MT）和 KRAS 野生型（KRAS-WT），并使用基因集富集分析计算相应的富集评分。最后，鉴定出具有最高通路活性的细胞亚群，使用 inferCNV 包对该亚群的拷贝数变异谱进行注释，并利用 CMap 数据库对针对该亚群的药物进行预测。
KRAS 突变的 LUAD 上皮细胞中 PI3K/AKT/mTOR 通路活性较高，KRAS、PIK3CA、AKT1 和 PDPK1 表达较高。特别是，我们发现 KRAS-MT 中的通路活性和相关基因表达明显高于 KRAS-WT。我们在 GRB2 上皮细胞的一个亚群中鉴定出最高的通路活性，并且在其通路中存在扩增基因。最后，能够针对 GRB2 上皮细胞亚群的药物，如 wortmannin、palbociclib 和血管生成抑制剂，能够靶向该亚群。
本研究为 KRAS 突变导致 PI3K/AKT/mTOR 信号通路激活提供了基础理论。
