Abstract
Farnesylation is a lipid post-translational modification of proteins crucial for protein membrane anchoring and cellular signaling. Farnesyltransferase inhibitors (FTIs), such as tipifarnib, are being tested in cancer therapy. However, the full impact of FTIs on farnesylation substrates remains poorly understood, thus limiting their use in precision medicine. In this study, we performed a global proteomics analysis to investigate farnesylation and the effects of tipifarnib in lung cancer cell lines. Using metabolic labeling and mass spectrometry, we identified farnesylated proteins and mapped their subcellular localization. We also analyzed tipifarnib-dependent protein relocalization and proteome-wide changes. Key findings include the potential therapeutic value of FTIs for NRAS-mutated melanoma and GNAQ/GNA11-mutated uveal melanoma by inhibiting INPP5A farnesylation. Additionally, we identified a synergistic drug combination involving tipifarnib and a ferroptosis inducer and discovered PTP4A1 as a regulator of interferon signaling. Our data, covering 15,080 proteins, offer valuable insights for future studies of farnesylation and FTIs.