文章：

协同靶向AXL与SRC对耐药性KRAS突变非小细胞肺癌的协同抑制作用

Synergistic Inhibition of Drug Resistant KRAS Mutant Non-Small Cell Lung Cancer by Co-Targeting AXL and SRC

原文发布日期：1 February 2025

DOI: 10.3390/cancers17030490

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: KRAS-mutated NSCLC has been targeted using monoclonal antibody (mAb) or tyrosine kinase inhibitor (TKI) therapies. However, in time, these mutations appear to develop resistance against the targeted antibodies and TKI treatments. One possible explanation is the activation of pro apoptotic pathways through the AXL–SRC–Akt axis. In this study, we identify AXL as the bypass resistant gene and investigate its role with KRAS and SRC activity. Methods: In this study, we use Dasatinib and SGI-7079 to co-inhibit SRC and AXL respectively. In vitro studies were conducted using four cell lines, and AXL suppression was achieved using siRNA and in CRISPR-Cas9 mediated knockout models. Subsequently, we studied gene-protein expression analysis using Western blot, apoptotic markers using a cytochrome release assay and cytotoxicity using an MTT assay. A549 xenografts were studied for in vivo validation of our proposed hypothesis. Results: The results suggest that dual inhibition of AXL and SRC significantly reversed this resistance, both in in vivo and in vitro studies. Conclusions: Co-inhibition of AXL and SRC synergistically reduced KRAS activity and induced apoptosis in NSCLC.

摘要翻译： 

背景/目的：针对KRAS突变的非小细胞肺癌（NSCLC），临床上已采用单克隆抗体（mAb）或酪氨酸激酶抑制剂（TKI）进行治疗。然而，随着时间的推移，这些突变似乎会对靶向抗体和TKI治疗产生耐药性。一种可能的解释是通过AXL–SRC–Akt轴激活促凋亡通路。本研究将AXL确定为旁路耐药基因，并探讨其与KRAS及SRC活性的关系。方法：本研究分别使用达沙替尼（Dasatinib）和SGI-7079共同抑制SRC和AXL。体外实验采用四种细胞系进行，并通过siRNA及CRISPR-Cas9介导的敲除模型实现AXL抑制。随后，我们通过Western blot进行基因-蛋白表达分析，通过细胞色素释放实验检测凋亡标志物，并通过MTT实验评估细胞毒性。利用A549异种移植模型进行体内实验以验证所提出的假设。结果：体内外研究均表明，同时抑制AXL和SRC能显著逆转这种耐药性。结论：AXL与SRC的协同抑制可降低KRAS活性并诱导非小细胞肺癌细胞凋亡。

原文链接：

Synergistic Inhibition of Drug Resistant KRAS Mutant Non-Small Cell Lung Cancer by Co-Targeting AXL and SRC