Expression and Clinical Significance of mTOR in Surgically Resected Non-small Cell Lung Cancer Tissues: a Case Control Study

  • Liu, Zhe (Department of Oncology, Beijing Chest Hospital, Capital Medical University of China) ;
  • Wang, Liang (Department of Molecular Biology Laboratory, Beijing Chest Hospital, Capital Medical University of China) ;
  • Zhang, Li-Na (Department of Molecular Biology Laboratory, Beijing Chest Hospital, Capital Medical University of China) ;
  • Wang, Yue (Department of Molecular Biology Laboratory, Beijing Chest Hospital, Capital Medical University of China) ;
  • Yue, Wen-Tao (Department of Molecular Biology Laboratory, Beijing Chest Hospital, Capital Medical University of China) ;
  • Li, Qi (Department of Oncology, Beijing Chest Hospital, Capital Medical University of China)
  • Published : 2012.12.31


Aims: Mammalian target of rapamycin (mTOR) is master regulator of the PI3K/Akt/mTOR pathway and plays an important role in NSCLCs. Here we characterized mRNA and protein expression levels of mTOR and its functional associated molecules including PTEN, IGF-1R and 4EBP1 in surgically resected NSCLCs. Methods: Fifty-four patients with NSCLCs who underwent pulmonary resection were included in current study. mRNA levels of mTOR, PTEN, IGF-1R, and 4EBP1 were evaluated by RT-PCR and protein expression of mTOR, PTEN, and IGF-1R by immunohistochemistry (IHC). Association of expression of the relevant molecules with clinical characteristics, as well as correlations between mTOR and PTEN, 4EBP1 and IGF-1R were also assessed. Results: The results of RT-PCR showed that in NSCLCs, the expression level of mTOR increased, while PTEN, 4EBP1 and IGF-1R decreased. Statistical analysis indicated high IGF-1R expression was correlated with advanced clinical stage (stage III) and PTEN expression was reversely associated with tumor size (P=0.16). The results of IHC showed mTOR positive staining in 51.8% of cases, while IGF-1R positive staining was found in 83.3% and loss of PTEN in 46.3%. Protein expression of mTOR was correlated with its regulators, PTEN and IGF-1R, to some extent. Conclusions: Abnormal activation of mTOR signaling, high expression of IGF-1R, and loss of PTEN were observed in resected NSCLC specimens. The poor expression agreement of mTOR with its regulators, PTEN, and IGF-1R, implied that combination strategy of mTOR inhibitors with other targets hold significant potential for NSCLC treatment.




  1. Price KA, Azzoli CG, Krug LM, et al (2010). Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer. J Thorac Oncol, 5, 1623-9.
  2. Quek R, Wang Q, Morgan JA, et al (2011). Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors. Clin Cancer Res, 17, 871-9.
  3. Schmid K, Bago-Horvath Z, Berger W, et al (2010). Dual inhibition of EGFR and mTOR pathways in small cell lung cancer. Br J Cancer, 103, 622-8.
  4. Shaw RJ, Cantley LC (2006). Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature, 441, 424-30.
  5. Steck PA, Pershouse MA, Jasser SA, et al (1997). Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet, 15, 356-62.
  6. Tang JM, He QY, Guo RX, Chang XJ (2006). Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer, 51, 181-91.
  7. Tarhini A, Kotsakis A, Gooding W, et al (2010). Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res, 16, 5900-7.
  8. Wang X, Beugnet A, Murakami M, et al (2005). Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. Mol Cell Biol, 25, 2558-72.
  9. Witzig TE, Reeder CB, LaPlant BR, et al (2011). A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia, 25, 341-7.
  10. Yuan R, Kay A, Berg WJ, Lebwohl D (2009). Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol, 2, 45.
  11. Balsara BR, Pei J, Mitsuuchi Y, et al (2004). Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis, 25, 2053-9.
  12. Cappuzzo F, Tallini G, Finocchiaro G, et al (2010). Insulin-like growth factor receptor 1 (IGF1R) expression and survival in surgically resected non-small-cell lung cancer (NSCLC) patients. Ann Oncol, 21, 562-7.
  13. Caron E, Ghosh S, Matsuoka Y, et al (2010). A comprehensive map of the mTOR signaling network. Mol Syst Biol, 6, 453.
  14. Dowling RJ, Pollak M, Sonenberg N (2009). Current status and challenges associated with targeting mTOR for cancer therapy. Bio Drugs, 23, 77-91.
  15. Dowling RJ, Topisirovic I, Alain T, et al (2010). mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science, 328, 1172-6.
  16. Dziadziuszko R, Merrick DT, Witta SE, et al (2010). Insulin-like growth factor receptor 1 (IGF1R) gene copy number is associated with survival in operable non-small-cell lung cancer: a comparison between IGF1R fluorescent in situ hybridization, protein expression, and mRNA expression. J Clin Oncol, 28, 2174-80.
  17. Efeyan A, Sabatini DM (2010). mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol, 22, 169-76.
  18. Guertin DA, Guntur KV, Bell GW, et al (2006). Functional genomics identifies TOR-regulated genes that control growth and division. Curr Biol, 16, 958-70.
  19. Heitman J, Movva NR, Hall MN (1991). Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science, 253, 905-9.
  20. Iwanaga K, Yang Y, Raso MG, et al (2008). Pten inactivation accelerates oncogenic K-ras-initiated tumorigenesis in a mouse model of lung cancer. Cancer Res, 68, 1119-27.
  21. Jemal A, Siegel R, Ward E, et al (2007). Cancer statistics, 2007. CA Cancer J Clin, 57, 43-66.
  22. Jiang BH, Liu LZ (2009). PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res, 102, 19-65.
  23. Milton DT, Riely GJ, Azzoli CG, et al (2007). Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer, 110, 599-605.
  24. Pfister DG, Johnson DH, Azzoli CG, et al (2004). American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol, 22, 330-53.
  25. Pollak M (2008). Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer, 8, 915-28.

Cited by

  1. Analysis of ICU Treatment on Resection of Giant Tumors in the Mediastinum of the Thoracic Cavity vol.14, pp.6, 2013,