Integrated Analysis of Single-cell and Bulk-RNA Sequencing Data to Identify Redox-related Genes as Prognostic Biomarkers and Therapeutic Targets of Lung Adenocarcinoma With Osimertinib Resistance.

IF 3.1 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chen Fang, Chaoxing Liu, Rong Qi, Jiabin Ding, Ting Luo, Feng Yu, Guohua Zhang, Chao Shi, Daya Luo, Feng Qiu
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Abstract

Background: Acquired resistance limits the therapeutic efficacy of osimertinib in lung adenocarcinoma (LUAD). Redox homeostasis is crucial for LUAD progression. However, how redox imbalance interacts with the tumor microenvironment (TME) to drive osimertinib resistance (OR) remains unclear.

Methods: The single-cell RNA sequencing (scRNA-seq) data GSE243562 were combined with the Cancer Genome Atlas (TCGA)-LUAD transcriptomes to map the TME cell population heterogeneity in osimertinib-resistant LUAD. Through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regularization, a prognostic signature founded on redox-related genes (RRGs) was built. Therapeutic compounds targeting these signature genes were prioritized by molecular docking. Their expression patterns were subsequently validated in vitro.

Results: Cancer-associated fibroblasts (CAFs) were central hubs in the TME of osimertinib-resistant LUAD, exhibiting enhanced intercellular communication. Computational profiling identified 10 differentially expressed RRGs, predominantly enriched in CAFs. Using a six-gene signature comprising AGER, CYP2J2, FMO2, HSPA1B, SOD3, and VASN, we categorized LUAD patients into separate risk categories. High-risk patients showed significantly reduced survival, an immunosuppressive status, and a higher tumor mutation burden (p < 0.05). The overexpression of these six genes was confirmed in OR cells. Critically, inhibiting SOD3 restored osimertinib sensitivity in vitro (p < 0.05). Clinically, SOD3 expression was lower in patients sensitive to third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) than in those with resistant disease.

Conclusions: Targeting CAFs represents a promising strategy to overcome osimertinib resistance. Our six-gene redox signature offers a clinical framework for patient risk stratification and novel therapeutic strategy design. Future work will explore these targets to develop new treatments for LUAD.

单细胞和大体积rna测序数据的综合分析,以确定氧化还原相关基因作为奥西替尼耐药肺腺癌的预后生物标志物和治疗靶点。
背景:获得性耐药限制了奥希替尼治疗肺腺癌(LUAD)的疗效。氧化还原稳态对LUAD的进展至关重要。然而,氧化还原失衡如何与肿瘤微环境(TME)相互作用以驱动奥西替尼耐药性(OR)仍不清楚。方法:将单细胞RNA测序(scRNA-seq)数据GSE243562与癌症基因组图谱(TCGA)-LUAD转录组相结合,绘制奥西替尼耐药LUAD的TME细胞群异质性。通过单变量Cox回归和最小绝对收缩和选择算子(LASSO)正则化,建立了基于氧化还原相关基因(RRGs)的预后特征。靶向这些特征基因的治疗化合物通过分子对接被优先排序。随后在体外验证了它们的表达模式。结果:癌症相关成纤维细胞(CAFs)是奥西替尼耐药LUAD TME的中心枢纽,表现出增强的细胞间通讯。计算分析鉴定出10个差异表达的RRGs,主要富集在caf中。使用包括AGER、CYP2J2、FMO2、HSPA1B、SOD3和VASN在内的6个基因标记,我们将LUAD患者分为不同的风险类别。高危患者生存率明显降低,免疫抑制,肿瘤突变负担加重(p < 0.05)。在OR细胞中证实了这6个基因的过表达。关键是,抑制SOD3可以恢复体外对奥希替尼的敏感性(p < 0.05)。临床上,对第三代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)敏感的患者中SOD3的表达低于耐药患者。结论:靶向caf是克服奥西替尼耐药的一种有希望的策略。我们的六基因氧化还原特征为患者风险分层和新的治疗策略设计提供了临床框架。未来的工作将探索这些靶点,以开发新的LUAD治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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