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Article

Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds

  • Authors:
    • Yu Huang
    • Yu Chen
    • Qin Mei
    • Yuan Chen
    • Shiying Yu
    • Shu Xia
  • View Affiliations / Copyright

    Affiliations: Cancer Center of Tongji Hospital, Tongji Medical College, Huazhong University of science and technology, Wuhan, Hubei 430030, P.r. China
  • Pages: 2486-2492
    |
    Published online on: March 22, 2013
       https://doi.org/10.3892/or.2013.2357
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Abstract

The epidermal growth factor receptor (EGFR) signaling pathway is widely activated in non-small cell lung cancer (NSCLC). However, only a subset of patients with NSCLC is sensitive to EGFR tyrosine kinase inhibitors (TKIs), particularly those with activating EGFR mutations. The mammalian target of rapamycin (mTOR) is another key intracellular kinase that plays an important role in the onset and progression of many types of human cancers and has been proven to be linked with primary resistance to EGFR inhibitors. We performed this study to investigate the combined inhibitory effect of the mTOR inhibitor RAD001 and the EGFR-TKI gefitinib in three EGFR wild-type NSCLC cell lines: A549 (PIK3CA wild‑type), NCI-H460 (PIK3CA mutant) and NCI-H661 (PIK3CA wild-type). All cell lines demonstrate a poor response to gefitinib, but have a different genetic status for PIK3CA. We used MTT assays to measure cell proliferation. Flow cytometry was used to assess the effects on apoptosis and cell cycle arrest. Immunoblot analysis was used to evaluate the expression of downstream proteins. Treatment of RAD001 alone showed dose-dependent growth inhibition in all three cell lines. The combination of gefitinib and RAD001 resulted in synergistic growth inhibition in NCI-H460 cells, but only an additive inhibitory effect on A549 and NCI-H661 cells. Exposure to the combination of RAD001 and gefitinib led to a significant reduction in phosphorylated AKT levels in NCI-H460 cells; however, this was not noted in the other two cell lines. In conclusion, our data indicate that the dual inhibition of the EGFR/mTOR pathways may be a promising approach to treat EGFR wild-type NSCLC; however, this may be dependent on the PIK3CA mutation status.
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1 

Sharma SV, Bell DW, Settleman J and Haber DA: Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 7:169–181. 2007. View Article : Google Scholar : PubMed/NCBI

2 

Wheeler DL, Dunn EF and Harari PM: Understanding resistance to EGFR inhibitors - impact on future treatment strategies. Nat Rev Clin Oncol. 7:493–507. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Han SW, Kim TY, Hwang PG, et al: Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small cell lung cancer patients treated with gefitinib. J Clin Oncol. 23:2493–2501. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Chakravarti A, Loeffler JS and Dyson NJ: Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res. 62:200–207. 2002.

5 

Engelman JA, Janne PA and Mermel C: ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA. 102:3788–3793. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Gorzalczany Y, Gilad Y, Amihai D, Hammel I, Sagi-Eisenberg R and Merimsky O: Combining an EGFR directed tyrosine kinase inhibitor with autophagy-inducing drugs: a beneficial strategy to combat non-small cell lung cancer. Cancer Lett. 310:207–215. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Morrow PK, Wulf GM, Ensor J, et al: Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol. 29:3126–3132. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G, Marciano R, Ciardiello F and Tortora G: Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer. 98:923–930. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Zoncu R, Efeyan A and Sabatini DM: mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 12:21–35. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Yea SS and Fruman DA: Cell signaling. New mTOR targets Grb attention. Science. 332:1270–1271. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Atkins MB, Yasothan U and Kirkpatrick P: Everolimus. Nat Rev Drug Discov. 8:535–536. 2009. View Article : Google Scholar : PubMed/NCBI

12 

Mordant P, Loriot Y, Leteur C, et al: Dependence on phosphoinositide 3-kinase and RAS-RAF pathways drive the activity of RAF265, a novel RAF/VEGFR2 inhibitor, and RAD001 (Everolimus) in combination. Mol Cancer Ther. 9:358–368. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Goldoni M and Johansson C: A mathematical approach to study combined effects of toxicants in vitro: evaluation of the Bliss independence criterion and the Loewe additivity model. Toxicol In Vitro. 21:759–769. 2007. View Article : Google Scholar : PubMed/NCBI

14 

Noro R, Gemma A, Kosaihira S, et al: Gefitinib (Iressa) sensitive lung cancer cell lines show phosphorylation of Akt without ligand stimulation. BMC Cancer. 6:2772006. View Article : Google Scholar : PubMed/NCBI

15 

Di Nicolantonio F, Arena S, Tabernero J, et al: Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 120:2858–2866. 2010.PubMed/NCBI

16 

Balko JM, Jones BR, Coakley VL and Black EP: Combined MEK and EGFR inhibition demonstrates synergistic activity in EGFR-dependent NSCLC. Cancer Biol Ther. 8:522–530. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Janmaat ML, Kruyt FA, Rodriguez JA and Giaccone G: Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res. 9:2316–2326. 2003.

18 

Dobashi Y, Suzuki S, Kimura M, et al: Paradigm of kinase-driven pathway downstream of epidermal growth factor receptor/Akt in human lung carcinomas. Human Pathol. 42:214–226. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Yu Y, Yoon SO, Poulogiannis G, et al: Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science. 332:1322–1326. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Hsu PP, Kang SA, Rameseder J, et al: The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 332:1317–1322. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Shi Y, Yan H, Frost P, Gera J and Lichtenstein A: Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther. 4:1533–1540. 2005. View Article : Google Scholar

22 

Goudar RK, Shi Q, Hjelmeland MD, et al: Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther. 4:101–112. 2005.

23 

Gemmill RM, Zhou M, Costa L, Korch C, Bukowski RM and Drabkin HA: Synergistic growth inhibition by Iressa and rapamycin is modulated by VHL mutations in renal cell carcinoma. Br J Cancer. 92:2266–2277. 2005. View Article : Google Scholar : PubMed/NCBI

24 

Price KA, Azzoli CG, Krug LM, et al: Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer. J Thorac Oncol. 5:1623–1629. 2010. View Article : Google Scholar : PubMed/NCBI

25 

La Monica S, Galetti M, Alfieri RR, et al: Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines. Biochem Pharmacol. 78:460–468. 2009.PubMed/NCBI

26 

Vienna L, Fortunato B, Lorenza P, et al: Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J Thorac Oncol. 6:707–715. 2011. View Article : Google Scholar

27 

Elizabeth B, Alexandra E, Eric B, et al: Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther. 5:2627–2684. 2006.PubMed/NCBI

28 

Magali R, Paul P, Amelie D, et al: Mechanisms underlying resistance to cetuximab in the HNSCC cell line: role of AKT inhibition in by passing this resistance. Int J Oncol. 38:189–200. 2011.PubMed/NCBI

29 

Tamburini J, Green AS and Bardet V: Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia. Blood. 114:1618–1627. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Mohseni M and Park BH: PIK3CA and KRAS mutations predict for response to everolimus therapy: now that's RAD001. J Clin Invest. 120:2655–2658. 2010. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Huang Y, Chen Y, Mei Q, Chen Y, Yu S and Xia S: Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds. Oncol Rep 29: 2486-2492, 2013.
APA
Huang, Y., Chen, Y., Mei, Q., Chen, Y., Yu, S., & Xia, S. (2013). Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds. Oncology Reports, 29, 2486-2492. https://doi.org/10.3892/or.2013.2357
MLA
Huang, Y., Chen, Y., Mei, Q., Chen, Y., Yu, S., Xia, S."Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds". Oncology Reports 29.6 (2013): 2486-2492.
Chicago
Huang, Y., Chen, Y., Mei, Q., Chen, Y., Yu, S., Xia, S."Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds". Oncology Reports 29, no. 6 (2013): 2486-2492. https://doi.org/10.3892/or.2013.2357
Copy and paste a formatted citation
x
Spandidos Publications style
Huang Y, Chen Y, Mei Q, Chen Y, Yu S and Xia S: Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds. Oncol Rep 29: 2486-2492, 2013.
APA
Huang, Y., Chen, Y., Mei, Q., Chen, Y., Yu, S., & Xia, S. (2013). Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds. Oncology Reports, 29, 2486-2492. https://doi.org/10.3892/or.2013.2357
MLA
Huang, Y., Chen, Y., Mei, Q., Chen, Y., Yu, S., Xia, S."Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds". Oncology Reports 29.6 (2013): 2486-2492.
Chicago
Huang, Y., Chen, Y., Mei, Q., Chen, Y., Yu, S., Xia, S."Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds". Oncology Reports 29, no. 6 (2013): 2486-2492. https://doi.org/10.3892/or.2013.2357
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