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<p><i>RAS</i> 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).</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月12日

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  • Guancong Luo,
  • Dexuan Li,
  • Jun Peng,
  • Rongsheng Liu,
  • Yajing Meng,
  • Richard Ward,
  • Yangyang Zhang,
  • Xinyu Zhang,
  • Fengxian Cui,
  • Jiwei Wang,
  • Xiuyu Yang,
  • Mo Chen,
  • Yanjun Xu,
  • Sheng Chen,
  • Wenyu Jiang,
  • Le Zhang,
  • Yurong Li,
  • Yang Yang,
  • Cheng Xiang,
  • Xiaoxi Guo,
  • Jiameng Dai,
  • Jun Sang,
  • Tian-Rui Xu,
  • Su An

摘要

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).