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- W2051474057 abstract "We recently demonstrated the ability of lovastatin to inhibit the function of the epidermal growth factor receptor (EGFR) and its downstream signaling of the PI3K/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in various tumor-derived cell lines. In this study, lovastatin treatment inhibits ligand-induced EGFR dimerization in squamous cell carcinoma (SCC) cells and its activation of AKT and its downstream targets 4EBP1 and S6K1. This inhibition was associated with global protein translational inhibition demonstrated by a decrease in RNA-associated polysome fractions. The effects of lovastatin on EGFR function were reversed by the addition of the geranylgeranyl pyrophosphate that acts as a protein membrane anchor. Lovastatin treatment induced actin cytoskeletal disorganization and the expression of the geranylgeranylated rho family proteins that regulate the actin cytoskeleton, including rhoA. Lovastatin-induced rhoA was inactive as EGF stimulation failed to activate rhoA and inhibition of the rho-associated kinase, a target and mediator of rhoA function, with Y-27632 also showed inhibitory effects on EGFR dimerization. The ability of lovastatin to inhibit EGFR dimerization is a novel exploitable mechanism regulating this therapeutically relevant target. To assess the potential of this approach, we evaluated the effect of statin use in patients enrolled in the BR21 erlotinib phase III study in non-small cell carcinoma (NSCLC) patients. In the erlotinib arm of this trial, although not statistically significant due to the limited number of patients on statins, in general, patients that were on statins performed better than patients without statins. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A53." @default.
- W2051474057 created "2016-06-24" @default.
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- W2051474057 date "2010-07-15" @default.
- W2051474057 modified "2023-09-27" @default.
- W2051474057 title "Abstract A53: Lovastatin inhibits EGFR dimerization and AKT activation in squamous cell carcinoma cells: Potential regulation through targeting rho proteins" @default.
- W2051474057 doi "https://doi.org/10.1158/1078-0432.tcmusa10-a53" @default.
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