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

Oncogene volume 29, pages 4682–4692 (2010)Cite this article

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Abstract

We recently showed the ability of lovastatin to inhibit the function of the epidermal growth factor receptor (EGFR) and its downstream signaling of the phosphatidylinositol-3 kinase/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in various tumor-derived cell lines. In this study, lovastatin treatment was found to inhibit ligand-induced EGFR dimerization in squamous cell carcinoma cells and its activation of AKT and its downstream targets 4E-binding protein 1 and S6 kinase 1. This inhibition was associated with global protein translational inhibition shown by a decrease in RNA associated polysome fractions. The effects of lovastatin on EGFR function were reversed by the addition of geranylgeranyl pyrophosphate, which functions as a protein membrane anchor. Lovastatin treatment induced actin cytoskeletal disorganization and the expression of 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 explore the potential clinical significance of this combination, we evaluated the effect of statin on the overall survival (OS) and disease-specific survival (DSS) of patients with advanced non-small-cell lung cancer enrolled in the NCIC Clinical Trials Group phase III clinical trials BR21 (EGFR tyrosine kinase inhibitor erlotinib versus placebo) and BR18 (carboplatin and paclitaxel with or without the metalloproteinase inhibitor BMS275291). In BR18, use of statin did not affect OS or DSS. In BR21, patients showed a trend for improvement in OS (HR: 0.69, P=0.098) and DSS (HR: 0.62, P=0.048), but there was no statin × treatment interaction effect (P=0.34 and P=0.51 for OS and DSS, respectively).

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Abbreviations

DSS:

disease specific survival

EGFR:

epidermal growth factor receptor

FPP:

farnesyl pyrophosphate

GGPP:

geranylgeranyl pyrophosphate

NSCLC:

non-small-cell lung carcinoma

OS:

overall survival

ROCK:

rho-associated kinase

SCC:

squamous cell carcinoma

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Acknowledgements

Research support from the Canadian Institute of Health Research (JD) and the Ontario Institute for Cancer Research (JD) is greatly appreciated. We thank Dr D. Gray, Apotex Canada and AstraZeneca UK for generously providing the reagents used in this study.

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Authors and Affiliations

  1. Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada,

    T T Zhao, B G Le Francois & J Dimitroulakos

  2. Department of Medical Oncology, The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

    T T Zhao & G Goss

  3. The Faculty of Medicine and the Department of Biochemistry at the University of Ottawa, Ottawa, Ontario, Canada

    J Dimitroulakos

  4. NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada

    K Ding & P A Bradbury

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  1. T T Zhao
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Correspondence to J Dimitroulakos.

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Zhao, T., Le Francois, B., Goss, G. et al. Lovastatin inhibits EGFR dimerization and AKT activation in squamous cell carcinoma cells: potential regulation by targeting rho proteins. Oncogene 29, 4682–4692 (2010). https://doi.org/10.1038/onc.2010.219

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