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Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status

  • Lab Investigaton - Human/Animal Tissue
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Abstract

The epidermal growth factor receptor (EGFR) is commonly amplified and mutated in glioblastoma, making it a compelling therapeutic target. Recent reports have demonstrated clinical activity of the EGFR inhibitors gefitinib and erlotinib in a subset of glioblastoma patients. Co-expression of EGFRvIII, a constitutively active mutant receptor expressed in 50% of tumours, and PTEN, an inhibitor of PI3K activity, by glioblastoma cells is associated with clinical response to these EGFR kinase inhibitors. PTEN loss and resulting increased PI3K pathway activity appears to act as a resistance factor. A critical therapeutic challenge is to identify agents that enhance the anti-cancer effects of these agents and promote responsiveness to EGFR kinase inhibitors in a broader spectrum of glioblastoma patients. For example, combining gefitinib with inhibitors of the PI3K/AKT pathway show enhanced cytotoxicity in glioblastoma derived cell lines. Here, we show that targeting HMG-CoA reductase with lovastatin, that can affect the activity of multiple cell signaling pathways, significantly enhanced the sensitivity of glioblastoma cells to the EGFR kinase inhibitor gefitinib in the five cell lines tested. In an isogenic model system, U87MG glioblastoma cells expressing EGFRvIII and PTEN in relevant combinations, we show that combined gefitinib and lovastatin treatments induce potent synergistic cytotoxicity irrespective of EGFRvIII and PTEN status. These studies demonstrate the potential of lovastatin to augment the cytotoxic effects of gefitinib and provide a rationale for combined statin/EGFR targeted therapies in glioblastoma patients.

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References

  1. Gschwind A, Zwick E, Prenzel N, Leserer M, Ullrich A (2001) Cell communication networks: epidermal growth factor receptor transactivation as the paradigm for interreceptor signal transmission. Oncogene 20:1594–1600

    Article  CAS  PubMed  Google Scholar 

  2. Pawson T (2002) Regulation and targets of receptor tyrosine kinases. Eur J Cancer 38(Suppl 5):S3–10

    Article  PubMed  Google Scholar 

  3. Mendelsohn J, Baselga J (2000) The EGF receptor family as targets for cancer therapy. Oncogene 19:6550–6565

    Article  CAS  PubMed  Google Scholar 

  4. Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC et al (1995) Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269:230–234

    Article  CAS  PubMed  Google Scholar 

  5. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW (2003) Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 284:31–53

    Article  CAS  PubMed  Google Scholar 

  6. Stern DF, Kamps MP (1988) EGF-stimulated tyrosine phosphorylation of p185neu: a potential model for receptor interactions. Embo J 7:995–1001

    CAS  PubMed  Google Scholar 

  7. Tan PB, Kim SK (1999) Signaling specificity: the RTK/RAS/MAP kinase pathway in metazoans. Trends Genet 15:145–149

    Article  CAS  PubMed  Google Scholar 

  8. Boulougouris P, Elder J (2001) Epidermal growth factor receptor structure, regulation, mitogenic signalling and effects of activation. Anticancer Res 21:2769–2775

    CAS  PubMed  Google Scholar 

  9. Herbst RS (2002) ZD1839: targeting the epidermal growth factor receptor in cancer therapy. Expert Opin Investig Drugs 11:837–849

    Article  CAS  PubMed  Google Scholar 

  10. Herbst RS (2003) Erlotinib (Tarceva): an update on the clinical trial program. Semin Oncol 30:34–46

    CAS  PubMed  Google Scholar 

  11. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139

    Article  CAS  PubMed  Google Scholar 

  12. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  CAS  PubMed  Google Scholar 

  13. Schwartzbaum JA, Fisher JL, Aldape KD, Wrensch M (2006) Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol 2:494–503

    Article  PubMed  Google Scholar 

  14. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, Kao JC, Stenzel TT, Ahmed Rasheed BK, Tourt-Uhlig SE, Herndon JE 2nd, Vredenburgh JJ, Sampson JH, Friedman AH, Bigner DD, Friedman HS (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133–142

    Article  CAS  PubMed  Google Scholar 

  15. Barber TD, Vogelstein B, Kinzler KW, Velculescu VE (2004) Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 351:2883

    Article  CAS  PubMed  Google Scholar 

  16. Frederick L, Wang XY, Eley G, James CD (2000) Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 60:1383–1387

    CAS  PubMed  Google Scholar 

  17. Li B, Yuan M, Kim IA, Chang CM, Bernhard EJ, Shu HK (2004) Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin. Oncogene 23:4594–4602

    Article  CAS  PubMed  Google Scholar 

  18. Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, O’Fallon JR, Schaefer PL, Scheithauer BW, James CD, Buckner JC, Jenkins RB (2001) PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93:1246–1256

    Article  CAS  PubMed  Google Scholar 

  19. Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, Tsurutani J, Dennis PA, Mills GB, Arteaga CL (2003) Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22:2812–2822

    Article  CAS  PubMed  Google Scholar 

  20. Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024

    Article  CAS  PubMed  Google Scholar 

  21. Wang MY, Lu KV, Zhu S, Dia EQ, Vivanco I, Shackleford GM, Cavenee WK, Mellinghoff IK, Cloughesy TF, Sawyers CL, Mischel PS (2006) Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res 66:7864–7869

    Article  CAS  PubMed  Google Scholar 

  22. Mantha AJ, Hanson JE, Goss G, Lagarde AE, Lorimer IA, Dimitroulakos J (2005) Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor. Clin Cancer Res 11:2398–2407

    Article  CAS  PubMed  Google Scholar 

  23. Mishima K, Johns TG, Luwor RB, Scott AM, Stockert E, Jungbluth AA, Ji XD, Suvarna P, Voland JR, Old LJ, Huang HJ, Cavenee WK (2001) Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor. Cancer Res 61:5349–5354

    CAS  PubMed  Google Scholar 

  24. Soneoka Y, Cannon PM, Ramsdale EE, Griffiths JC, Romano G, Kingsman SM, Kingsman AJ (1995) A transient three-plasmid expression system for the production of high titer retroviral vectors. Nucleic Acids Res 23:628–633

    Article  CAS  PubMed  Google Scholar 

  25. Dimitroulakos J, Yeger H (1996) HMG-CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: lovastatin specifically targets P-glycoprotein-expressing cells. Nat Med 2:326–333

    Article  CAS  PubMed  Google Scholar 

  26. Dimitroulakos J, Ye LY, Benzaquen M, Moore MJ, Kamel-Reid S, Freedman MH, Yeger H, Penn LZ (2001) Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications. Clin Cancer Res 7:158–167

    CAS  PubMed  Google Scholar 

  27. Jiang Z, Zheng X, Lytle RA, Higashikubo R, Rich KM (2004) Lovastatin-induced up-regulation of the BH3-only protein, Bim, and cell death in glioblastoma cells. J Neurochem 89:168–178

    Article  CAS  PubMed  Google Scholar 

  28. Piacentini M, Fesus L, Melino G (1993) Multiple cell cycle access to the apoptotic death programme in human neuroblastoma cells. FEBS Lett 320:150–154

    Article  CAS  PubMed  Google Scholar 

  29. Thibault A, Samid D, Tompkins AC, Figg WD, Cooper MR, Hohl RJ, Trepel J, Liang B, Patronas N, Venzon DJ, Reed E, Myers CE (1996) Phase 1 study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clinical Cancer Res 2:483–491

    CAS  Google Scholar 

  30. Dancey JE, Freidlin B (2003) Targeting epidermal growth factor receptor—are we missing the mark? Lancet 362:62–64

    Article  CAS  PubMed  Google Scholar 

  31. Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N (2006) mTOR, translation initiation and cancer. Oncogene 25:6416–6422

    Article  CAS  PubMed  Google Scholar 

  32. Corsini A, Maggi FM, Catapano AL (1995) Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res 31:9–27

    Article  CAS  PubMed  Google Scholar 

  33. Chan KK, Oza AM, Siu LL (2003) The statins as anticancer agents. Clin Cancer Res 9:10–19

    CAS  PubMed  Google Scholar 

  34. Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343:425–430

    Article  CAS  PubMed  Google Scholar 

  35. Gibbs JB, Oliff A, Kohl NE (1994) Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 77:175–178

    Article  CAS  PubMed  Google Scholar 

  36. Sebti S, Hamilton AD (1997) Inhibitors of prenyl transferases. Curr Opin Oncol 9:557–561

    Article  CAS  PubMed  Google Scholar 

  37. Keyomarsi K, Sandoval L, Band V, Pardee AB (1991) Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res 51:3602–3609

    CAS  PubMed  Google Scholar 

  38. Dimitroulakos J, Nohynek D, Backway KL, Hedley DW, Yeger H, Freedman MH, Minden MD, Penn LZ (1999) Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: a potential therapeutic approach. Blood 93:1308–1318

    CAS  PubMed  Google Scholar 

  39. Macaulay RJ, Wang W, Dimitroulakos J, Becker LE, Yeger H (1999) Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro. J Neurooncol 42:1–11

    Article  CAS  PubMed  Google Scholar 

  40. Knox JJ, Siu LL, Chen E, Dimitroulakos J, Kamel-Reid S, Moore MJ, Chin S, Irish J, LaFramboise S, Oza AM (2005) A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Eur J Cancer 41:523–530

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Research support from the Canadian Institute of Health Research (J. D.), the Canadian Foundation for Innovation/Ontario Innovation Trust (J.D.) and the Ottawa Regional Cancer Foundation (J. D.). We wish to thank Apotex Canada and AstraZeneca UK for generously providing reagents used in this study.

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Authors and Affiliations

  1. Centre for Cancer Therapeutics, The Ottawa Health Research Institute and Ottawa Regional Cancer Centre, 503 Smyth Road, Third Floor, Ottawa, ON, Canada, K1H 1C4

    Catia Cemeus, Tong T. Zhao, Gordon M. Barrett, Ian A. Lorimer & Jim Dimitroulakos

  2. The Faculty of Medicine, Department of Biochemistry, University of Ottawa, Ottawa, ON, Canada

    Tong T. Zhao, Ian A. Lorimer & Jim Dimitroulakos

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  1. Catia Cemeus
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  2. Tong T. Zhao
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Correspondence to Jim Dimitroulakos.

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Cemeus, C., Zhao, T.T., Barrett, G.M. et al. Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status. J Neurooncol 90, 9–17 (2008). https://doi.org/10.1007/s11060-008-9627-0

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  • DOI: https://doi.org/10.1007/s11060-008-9627-0

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