Farnesyltransferase inhibitor LB42708 disables oncogenic RAS signaling and overcomes gefitinib resistance in NSCLC via FTase α-subunit and RAS degradation

作者：Guancong Luo, Dexuan Li, Jun Peng, Rongsheng Liu, Yajing Meng, Richard Ward, Yangyang Zhang, Xinyu Zhang, Fengxian Cui, Jiwei Wang, Xiuyu Yang, Mo Chen, Ye Xu, Sheng Chen, Wenyu Jiang, Le Zhang, Yurong Li, Yang Yang, Cheng Xiang, Xiaoxi Guo, Jiameng Dai, Jun Sang, Tian‐Rui Xu, Su An · 发表于：Cell Communication and Signaling · 年份：2026 · DOI：10.1186/s12964-026-02798-z · 研究领域：Protein Kinase Regulation and GTPase Signaling、Protease and Inhibitor Mechanisms、Cancer Cells and Metastasis

RAS mutations are among the most common oncogenic drivers in human cancers, particularly in non-small cell lung cancer (NSCLC). Direct targeting of RAS proteins remains difficult due to the lack of suitable drug-binding pockets on their surfaces. LB42708 is a potent and selective farnesyltransferase (FTase) inhibitor that disrupts RAS farnesylation and downstream signaling. This study evaluates the anti-tumor effects of LB42708 in KRAS- and HRAS-mutant NSCLC cells, as well as gefitinib-resistant PC9 (PC9GR) cells. LB42708 significantly inhibits the proliferation, migration, invasion, stemness, and clonal growth of RAS-mutant NSCLC cells, while inducing apoptosis and cell cycle arrest. The inhibitory effects are further validated in patient-derived organoids and xenograft models. Mechanistically, LB42708 suppresses FTase activity, reduces RAS protein levels through proteasome-dependent degradation, and induces caspase-3–mediated degradation of the shared α-subunit of FTase and geranylgeranyltransferase-1 (GGTase-1). Combination treatment with LB42708 and the AKT inhibitor AZD5363 (capivasertib) produces synergistic anti-tumor activity in RAS-mutant NSCLC. Moreover, LB42708 enhances the sensitivity of PC9GR cells to gefitinib. Collectively, these findings demonstrate that LB42708, alone or in combination with AZD5363 or gefitinib, represents as a promising therapeutic candidate for NSCLC harboring RAS mutations or resistant to tyrosine kinase inhibitors (TKIs). Mutations in a f...