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

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 family of genes called RAS are among the most common causes of cancer, especially non-small cell lung cancer (NSCLC). These mutations make cancer cells grow and spread uncontrollably. Unfortunately, RAS proteins are very hard to target directly with drugs because they lack good binding sites. In this study, we tested a compound called LB42708, which blocks an enzyme known as farnesyltransferase (FTase). This enzyme helps RAS proteins attach to cell membranes, a step that is essential for their cancer-promoting activity. By inhibiting FTase, LB42708 prevents RAS from functioning properly. We found that LB42708 strongly reduced the growth, movement, and stem cell–like behavior of lung cancer cells carrying KRAS or HRAS mutations. It also caused these cancer cells to stop dividing and undergo cell death. The same effects were observed in patient-derived tumor organoids and mouse models of lung cancer. Further experiments showed that LB42708 not only blocks FTase activity but also promotes the breakdown of RAS proteins through the cell’s natural protein degradation system, while also triggering caspase-3–mediated degradation of the FTase α-subunit, a key component required for RAS activation. When used together with another drug, AZD5363 (capivasertib), which inhibits the AKT signaling pathway, LB42708 produced even stronger anti-cancer effects. It also restored sensitivity to gefitinib, a drug that many lung cancers become resistant to. Overall, our results suggest that LB42708, either alone or in combination with other targeted therapies, could be a promising new treatment option for lung cancers with RAS mutations or drug resistance.