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

Authors' Affiliations: ¹ Centre for Cancer Therapeutics and ² Medical Oncology, Ottawa Hospital Regional Cancer Centre and Ottawa Health Research Institute; and ³ Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

Requests for reprints: Jim Dimitroulakos, Centre for Cancer Therapeutics, Ottawa Regional Cancer Centre, 503 Smyth Road, Third Floor, Ottawa, Ontario, Canada K1H 1C4. Phone: 613-737-7700, ext. 70335; Fax: 613-247-3524; E-mail: jdimitroulakos{at}ohri.ca.

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 non–small 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.