Multi-Omics and Single-Cell Insights Reveal a Lysophosphatidic Acid (LPA)-Mediated Resistant Mechanism to Third Generation EGFR-TKI in Non-Small Cell Lung Cancer

IF 10.2 1区医学 Q1 ONCOLOGY

Clinical Cancer Research Pub Date : 2025-08-25 DOI:10.1158/1078-0432.ccr-25-0993

Ruyun Gao, Ning Lou, Sheng Yang, Mengwei Yang, Guangyu Fan, Liyuan Dai, Le Tang, Jiarui Yao, Xiaohong Han, Yuankai Shi

{"title":"Multi-Omics and Single-Cell Insights Reveal a Lysophosphatidic Acid (LPA)-Mediated Resistant Mechanism to Third Generation EGFR-TKI in Non-Small Cell Lung Cancer","authors":"Ruyun Gao, Ning Lou, Sheng Yang, Mengwei Yang, Guangyu Fan, Liyuan Dai, Le Tang, Jiarui Yao, Xiaohong Han, Yuankai Shi","doi":"10.1158/1078-0432.ccr-25-0993","DOIUrl":null,"url":null,"abstract":"Introduction: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of EGFR-sensitive-mutant non-small cell lung cancer (NSCLC). However, acquired resistance remains a significant challenge. This study investigates the metabolic mechanisms driving third-generation EGFR-TKI resistance. Methods: We conducted plasma metabolomics analysis on 216 longitudinal samples from 186 NSCLC patients enrolled in the clinical trial of rezivertinib (NCT03386955). Additionally, multi-omics profiling of rezivertinib-resistant cell lines, functional in vitro experiments, and single-cell RNA sequencing (scRNA-seq) analyses of 215 NSCLC patients were integrated to reveal underlying mechanisms. Results: Non-responder patients exhibited elevated glycerophospholipids and dysregulated lysophospholipid (LPL) metabolism. Unsupervised clustering identified two patient subgroups, with Cluster 1 (characterized by high LPL levels) associated with poorer survival (P = 0.022). Metabolite-based predictive model achieved robust performance (AUC: 0.7762 [training], 0.7485 [test]). Longitudinal analyses demonstrated LPLs and lysophosphatidic acid (LPA) accumulation during the resistance process. Integrated multi-omics analyses highlighted epithelial-mesenchymal transition (EMT) and glycerophospholipid reprogramming in rezivertinib-resistant cells. Functional assays confirmed that LPA promoted cell migration and invasion, and attenuated the efficacy of third-generation EGFR-TKI, while disruption of the LPA-LPAR signaling axis reversed LPA-mediated resistance. scRNA-seq identified an LPA-secreting malignant subset (cluster c4), characterized by enhanced EMT activation and extensive microenvironmental crosstalk through Wnt, TGF-β, and ECM signals. Conclusions: Our study highlights the pivotal role of LPA-mediated signaling and metabolic reprogramming in third-generation EGFR-TKI resistance. Targeting LPA production or its downstream pathways may offer novel therapeutic strategies to overcome resistance. This study provides critical metabolic insights for managing EGFR-sensitive-mutant NSCLC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"132 1","pages":""},"PeriodicalIF":10.2000,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1078-0432.ccr-25-0993","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Introduction: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of EGFR-sensitive-mutant non-small cell lung cancer (NSCLC). However, acquired resistance remains a significant challenge. This study investigates the metabolic mechanisms driving third-generation EGFR-TKI resistance. Methods: We conducted plasma metabolomics analysis on 216 longitudinal samples from 186 NSCLC patients enrolled in the clinical trial of rezivertinib (NCT03386955). Additionally, multi-omics profiling of rezivertinib-resistant cell lines, functional in vitro experiments, and single-cell RNA sequencing (scRNA-seq) analyses of 215 NSCLC patients were integrated to reveal underlying mechanisms. Results: Non-responder patients exhibited elevated glycerophospholipids and dysregulated lysophospholipid (LPL) metabolism. Unsupervised clustering identified two patient subgroups, with Cluster 1 (characterized by high LPL levels) associated with poorer survival (P = 0.022). Metabolite-based predictive model achieved robust performance (AUC: 0.7762 [training], 0.7485 [test]). Longitudinal analyses demonstrated LPLs and lysophosphatidic acid (LPA) accumulation during the resistance process. Integrated multi-omics analyses highlighted epithelial-mesenchymal transition (EMT) and glycerophospholipid reprogramming in rezivertinib-resistant cells. Functional assays confirmed that LPA promoted cell migration and invasion, and attenuated the efficacy of third-generation EGFR-TKI, while disruption of the LPA-LPAR signaling axis reversed LPA-mediated resistance. scRNA-seq identified an LPA-secreting malignant subset (cluster c4), characterized by enhanced EMT activation and extensive microenvironmental crosstalk through Wnt, TGF-β, and ECM signals. Conclusions: Our study highlights the pivotal role of LPA-mediated signaling and metabolic reprogramming in third-generation EGFR-TKI resistance. Targeting LPA production or its downstream pathways may offer novel therapeutic strategies to overcome resistance. This study provides critical metabolic insights for managing EGFR-sensitive-mutant NSCLC.

查看原文本刊更多论文

多组学和单细胞研究揭示溶血磷脂酸（LPA）介导的非小细胞肺癌对第三代EGFR-TKI的耐药机制

第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）已经彻底改变了EGFR敏感突变型非小细胞肺癌（NSCLC）的治疗。然而，获得性耐药性仍然是一个重大挑战。本研究探讨了驱动第三代EGFR-TKI耐药的代谢机制。方法：我们对186名参加瑞齐替尼（NCT03386955）临床试验的非小细胞肺癌患者的216份纵向样本进行了血浆代谢组学分析。此外，对215名NSCLC患者进行了rezivertinib耐药细胞系的多组学分析、体外功能实验和单细胞RNA测序（scRNA-seq）分析，以揭示潜在的机制。结果：无应答患者表现出甘油磷脂升高和溶血磷脂（LPL）代谢失调。无监督聚类确定了两个患者亚组，第1类（以高LPL水平为特征）与较差的生存率相关（P = 0.022）。基于代谢物的预测模型获得了稳健的性能（AUC: 0.7762 [training], 0.7485 [test]）。纵向分析表明LPLs和溶血磷脂酸（LPA）在抗性过程中积累。综合多组学分析强调了瑞济替尼耐药细胞的上皮-间质转化（EMT）和甘油磷脂重编程。功能分析证实，LPA促进了细胞迁移和侵袭，减弱了第三代EGFR-TKI的疗效，而LPA- lpar信号轴的破坏逆转了LPA介导的耐药性。scRNA-seq鉴定出一个分泌lpa的恶性亚群（簇c4），其特征是EMT激活增强，并通过Wnt、TGF-β和ECM信号进行广泛的微环境串扰。结论：我们的研究强调了lpa介导的信号传导和代谢重编程在第三代EGFR-TKI耐药中的关键作用。靶向LPA生产或其下游途径可能为克服耐药性提供新的治疗策略。这项研究为管理egfr敏感突变型非小细胞肺癌提供了关键的代谢见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Clinical Cancer Research 医学-肿瘤学

CiteScore

20.10

自引率

1.70%

发文量

1207

审稿时长

2.1 months

期刊介绍： Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.