Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor.
OBJECTIVE
The epidermal growth factor receptor (EGFR) is a key regulator of growth, differentiation, and survival of epithelial cancers. In a small subset of tumors, the presence of activating mutations within the ATP binding site confers increased susceptibility to gefitinib, a potent tyrosine kinase inhibitor of EGFR. Agents that can inhibit EGFR function through different mechanisms may enhance gefitinib activity in patients lacking these mutations. Mevalonate metabolites play significant roles in the function of the EGFR; therefore, mevalonate pathway inhibitors may potentiate EGFR-targeted therapies.


METHODS
In this study, we evaluated the effect of lovastatin on EGFR function and on gefitinib activity. Effects on EGFR function were analyzed by Western blot analysis using phosphospecific antibodies to EGFR, AKT, and extracellular signal-regulated kinase. Cytotoxic effects of lovastatin and/or gefitinib were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry.


RESULTS
Lovastatin treatment inhibited EGF-induced EGFR autophosphorylation by 24 hours that was reversed by the coadministration of mevalonate. Combining lovastatin and gefitinib treatments showed enhanced inhibition of AKT activation by EGF in SCC9 cells. The combination of 10 mumol/L lovastatin and 10 mumol/L gefitinib treatments showed cooperative cytotoxicity in all 8 squamous cell carcinomas, 4 of 4 non-small cell lung carcinoma and 4 of 4 colon carcinoma cell lines tested. Isobologram and flow cytometric analyses of three representative cell lines with wild-type EGFR ATP binding sites confirmed that this combination was synergistic inducing a potent apoptotic response.


CONCLUSIONS
Taken together, these results show that targeting the mevalonate pathway can inhibit EGFR function. They also suggest the potential utility of combining these clinically relevant therapeutic approaches.
Mantha
Angela J
AJ
Centre for Cancer Therapeutics and Medical Oncology, Ottawa Regional Cancer Centre, Ottawa Health Research Institute, 503 Smyth Road, Ottawa, Ontario, Canada K1H 1C4.
Hanson
Jennifer E L
JE
Goss
Glenwood
G
Lagarde
Alain E
AE
Lorimer
Ian A
IA
Dimitroulakos
Jim
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008148:Lovastatin / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008798:Mevalonic Acid / Q000737:chemistry* / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D011799:Quinazolines; D004815:Epidermal Growth Factor; D000255:Adenosine Triphosphate; D008148:Lovastatin; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D008798:Mevalonic Acid; D000077156:Gefitinib