Multiomics and Single-Cell Insights Reveal a Lysophosphatidic Acid–Mediated Resistant Mechanism to Third-generation EGFR-TKI in Non–Small Cell Lung Cancer

作者：Ruyun Gao, Ning Lou, Sheng Yang, Mengwei Yang, Guangyu Fan, Liyuan Dai, Le Tang, Jiarui Yao, Xiaohong Han, Yuankai Shi · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-0993 · 被引用次数：6 · 研究领域：Sphingolipid Metabolism and Signaling、Metabolomics and Mass Spectrometry Studies、Lung Cancer Treatments and Mutations

PURPOSE: Third-generation EGFR tyrosine kinase inhibitors (TKI) have revolutionized the treatment of EGFR-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. EXPERIMENTAL DESIGN: We conducted plasma metabolomics analysis on 216 longitudinal samples from 186 patients with NSCLC enrolled in the clinical trial of rezivertinib (NCT03386955). Additionally, multiomics profiling of rezivertinib-resistant cell lines, functional in vitro experiments, and single-cell RNA sequencing analyses of 215 patients with NSCLC were integrated to reveal underlying mechanisms. RESULTS: Nonresponder 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). A metabolite-based predictive model achieved robust performance [AUC: 0.7762 (training) and 0.7485 (test)]. Longitudinal analyses demonstrated LPLs and lysophosphatidic acid (LPA) accumulation during the resistance process. Integrated multiomics analyses highlighted epithelial-mesenchymal transition 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, whereas di...