Strategies to Enhance Epidermal Growth Factor Inhibition: Targeting the Mevalonate Pathway

Abstract

Mevalonate metabolites play an essential role in transducing epidermal growth factor (EGF) receptor (EGFR)^mediated signaling, as several of these metabolites are required for the function of this receptor and the components of its signaling cascades. Thus, the depletion of mevalonate metabolites may have a significant effect on EGFR function. Lovastatin is a specific and potent inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Targeting 3-hydroxy-3-methylglutaryl CoA reductase using lovastatin induces a potent tumor-specific apoptotic response in a variety of tumor types at therapeutically achievable levels of this drug. The effects of lovastatin on EGFR function and the potential combination effects with EGFR tyrosine kinase inhibitors, such as gefitinib, were evaluated. Lovastatin treatment inhibited EGF-induced EGFR autophosphorylation and its downstream signaling cascades by 24 hours. Combining lovastatin and gefitinib showed enhanced inhibition and cooperative cytotoxicity in a variety of cell lines that included all eight squamous cell carcinomas, four nonŝ mall cell lung carcinoma, and four colon carcinoma cell lines tested. Isobologram analyses confirmed that this combination was synergistic, inducing a potent apoptotic response. A phase I study has shown the safety and potential clinical benefit of high-dose lovastatin in patients with recurrent squamous cell carcinoma. The use of lovastatin, which is metabolized by CYP3A4, is contraindicated with drugs, such as gefitinib and erlotinib, which are also metabolized by CYP3A4 due to greatly enhanced toxicity. Rosuvastatin, a relatively novel potent mevalonate pathway inhibitor that is not metabolized significantly by CYP3A4, is a more appropriate statin to combine with either erlotinib or gefitinib. The combination of erlotinib and rosuvastatin has been proposed for a phase I/II study in advanced non^small cell lung carcinoma.The ErbB family of receptor proteins [ErbB1/epidermal growth factor (EGF) receptor (EGFR), ErbB2, ErbB3, and ErbB4] plays a key role in the growth, differentiation, migration, and cell survival of epithelial tissues (1, 2). These cell membrane receptors are functionally divided into three regions: an extracellular ligand-binding region, an intracellular region with tyrosine kinase activity and regulatory functions, and a region that spans the cell membrane and anchors the receptor to the cell (3). In the inactive state, each ErbB receptor exists as a monomer. Despite their high degree of structural homology, the ErbB receptors differ in their ligand specificities. EGFR, ErbB3, and ErbB4 are activated by a large family of ligands, with each receptor having differences in its ligand specificity (4).ErbB2 has no ligand but preexists in a conformation that allows it to heterodimerize with other ErbB family members (4). These ErbB2-containing heterodimers form the highest affinity binding sites for their respective ligands (4). Ligand binding to the EGFR promotes either hom...

A Randomized Phase II Study of Gefitinib Plus Simvastatin Versus Gefitinib Alone in Previously Treated Patients with Advanced Non–Small Cell Lung Cancer

“…To date, several preclinical studies have shown that the combination of statins with gefitinib induces a potent synergistic cytotoxicity in a variety of tumors without EGFR mutations (20,21). Recently, Zhao and colleagues reported that lovastatin inhibits ligand-induced EGFR dimerization in squamous cell head and neck carcinoma cells, which results in inhibition of AKT activation along with its downstream targets that regulate protein translation initiation.…”

“…The impact of statins on EGFR function and signaling and in vivo activity against tumor cells has generated interest in studying statins as a potential EGFRtargeted therapeutic intervention. Some in vitro studies have reported that the combination of gefitinib and lovastatin has synergistic cytotoxicity and enhances EGFR inhibition in squamous cell head and neck carcinoma, NSCLC, and colon carcinoma cell lines (20)(21)(22). Interestingly, not all of the studied cell lines possess EGFR mutations, which confer increased sensitivity to gefitinib.…”

Lovastatin inhibits EGFR dimerization and AKT activation in squamous cell carcinoma cells: potential regulation by targeting rho proteins

“…Combinations of statins with agents targeting EGFR activity, such as gefitinib, induce a potent synergistic cytotoxic response in a variety of responsive tumor types, including SCC (Mantha et al, 2005). Combining these two approaches, with each targeting the EGFR through distinct mechanisms, represents a novel combinational therapeutic approach in SCC, as well as in other cancers in which EGFR is involved in their pathogenesis (Dimitroulakos et al, 2006). Rationally designed combination therapies represent a potential strategy to improve their efficacy.…”

EGFR-Targeted Therapy in Malignant Glioma: Novel Aspects and Mechanisms of Drug Resistance

“…For example, several studies have provided evidence supporting the notion that inhibition of a dominant oncogene, such as EGFR/EGFRvIII, by targeted therapy can alter the hierarchy of RTKs and non-receptor TKs resulting in the activation of other TKs, such as, c-mesenchymal-epithelial transition factor (c-Met), platelet-derived growth factor receptor (PDGFR) and JAK2, in order to facilitate tumor survival [77,81,82]. Another potential mechanism of resistance can be derived from HMG-CoA reductase, the ratelimiting enzyme in the mevalonate pathway that produces metabolites to activate EGFR signaling [83,84]. Our laboratory has recently shown that the JAK2-STAT3 pathway is constitutively activated in the majority of GBMs and that STAT3 undergoes multi-level interactions with EGFR, leading to the resistance of GBM cells to Iressa [81].…”

“…The mevalonate pathway produces end products, such as, dolichol, cholesterol, geranylgeranyl pyrophosphate and farnesyl pyrophosphate that can directly affect EGFR activity, as well as, indirectly modulate the activity of EGFR-mediated downstream molecules [84]. Dolichol is involved in N-linked glycosylation of several RTKs [94] and the ligand-binding domain of EGFR is glycosylated to allow for ligand-binding, cell-surface localization and proper conformation [95].…”