Tricin selectively combats KRAS-mutant non-small cell lung cancer by inhibiting the PDGF-BB-induced SRC/MAPK/AP-1/PD-L1 signaling pathway and potentiating the antitumor effect of an anti-PD-1 antibody

作者：Jiaxin Li, Shiyu Tan, Li-Qi Li, Zheng Yu-hong, Lin Zhao, Huirong Zhu, Hailang He, Yanyu Zhang, Runze Li, Tian-Yu Bao, Yizhong Zhang, Xiaoman Yang, Hao Zhang, Huihui Chen, Bowen Wu, Xin Lin, Xiao‐Sheng Lin, Lin Ye, Xinbing Sui, Ying Xie, Xianmei Zhou, Peiyu Yan · 发表于：Frontiers in Pharmacology · 年份：2025 · DOI：10.3389/fphar.2025.1594213 · 被引用次数：2 · 研究领域：Endoplasmic Reticulum Stress and Disease、Protein Kinase Regulation and GTPase Signaling、Toxin Mechanisms and Immunotoxins

Background KRAS is a commonly mutated gene that is present in approximately 30% of NSCLC patients. Currently, the identification of effective therapies for KRAS-mutant NSCLC is difficult for reasons of the structural and biochemical characteristics of the KRAS protein. Our previous study has revealed that tricin was a bioactive component having selective effects on KRAS G12C -mutant NSCLC cell lines. Thus, our aim in this project was to explore the mechanism by which tricin inhibited the progression of KRAS-mutant NSCLC much more deeply. Methods First of all, we detected the acute toxicity of an intraperitoneal injection of tricin in mice according to the improved up-and-down procedure. Next, we integrated network pharmacology, molecular docking with transcriptomics analysis and biological methods to probe the underlying mechanisms of tricin in the treatment of patients with KRAS-mutant NSCLC. Furthermore, we explored the pharmaceutical effects of combination therapy with tricin and an anti-PD-1 inhibitor. Finally, we detected and analyzed the data from clinical samples to prepare for the clinical translation of tricin. Results Intraperitoneal injection of tricin resulted in low acute toxicity. In vitro , tricin inhibited the migration, proliferation and colony formation of KRAS G12C -mutant NSCLC cells in a dose-dependent manner. Mechanistically, tricin inhibited KRAS G12C -mutant NSCLC cell growth primarily by suppressing the PDGF-BB-induced SRC/MAPK/AP-1/PD-L1 signaling pa...