Advertisement

Annals of Surgical Oncology

, Volume 21, Supplement 4, pp 610–618 | Cite as

Cytoplasmic YAP Expression is Associated with Prolonged Survival in Patients with Lung Adenocarcinomas and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment

  • Ping-Li Sun
  • Ji Eun Kim
  • Seol Bong Yoo
  • Hyojin Kim
  • Yan Jin
  • Sanghoon Jheon
  • Kwhanmien Kim
  • Choon Taek Lee
  • Jin-Haeng Chung
Translational Research and Biomarkers

Abstract

Background

Yes-associated protein (YAP) has been reported to be associated with the prognosis of various cancers and also to affect epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR–TKI) activity in ovarian cancer cell lines. However, few studies have evaluated YAP protein expression in lung cancer, and the results have lacked consistency.

Methods

YAP expression was evaluated in a total of 205 curatively resected lung adenocarcinomas and 36 cases of EGFR-mutated TKI-treated patients. Correlations between the expression of YAP and clinicopathologic features, response to EGFR–TKI treatment, and prognostic significance were analyzed.

Results

High cytoplasmic YAP expression was positively correlated with the clinicopathologic parameters that have been associated with favorable prognosis. Multivariate analysis revealed that high cytoplasmic YAP expression was an independent prognostic factor in lung adenocarcinomas (progression-free survival: hazard ratio [HR] 0.659; 95 % confidence interval [CI] 0.431–1.010; p = 0.050; overall survival: HR, 0.474; 95 % CI 0.263–0.854; p = 0.013) and EGFR-TKI-treated patients with EGFR mutation (progression-free survival: HR, 0.346; 95 % CI 0.146–0.818; p = 0.016; overall survival: HR, 0.291; 95 % CI 0.125–0.676; p = 0.004).

Conclusions

High cytoplasmic YAP expression predicted a good clinical outcome for patients with lung adenocarcinoma and in EGFR–TKI-treated patients. Therefore, YAP may play a role in EGFR–TKI-treated lung cancer, and YAP targeting may enhance therapeutic effects in combination with other cancer drugs.

Keywords

Overall Survival Gefitinib Erlotinib Lung Adenocarcinoma EGFR Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

Supported in partly by Grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013-059757 to J.H.C. and 2011-0025344 to J.E.K.). The authors are indebted to J. Patrick Barron, professor emeritus, Tokyo Medical University, and adjunct professor, Seoul National University Bundang Hospital, for his pro bono editorial work.

Disclosure

The authors declare no conflict of interest.

Supplementary material

10434_2014_3715_MOESM1_ESM.tif (869 kb)
Supplementary material 1 (TIFF 868 kb)
10434_2014_3715_MOESM2_ESM.tif (108 kb)
Supplementary material 2 (TIFF 108 kb)
10434_2014_3715_MOESM3_ESM.doc (48 kb)
Supplementary material 3 (DOC 47 kb)

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRefGoogle Scholar
  2. 2.
    Mahalingam D, Mita A, Mita MM, Nawrocki ST, Giles FJ. Targeted therapy for advanced non–small cell lung cancers: historical perspective, current practices, and future development. Curr Probl Cancer. 2009;33:73–111.PubMedCrossRefGoogle Scholar
  3. 3.
    Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24:862–74.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Pan D. The hippo signaling pathway in development and cancer. Dev Cell. 2010;19:491–505.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Overholtzer M, Zhang J, Smolen GA, et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA. 2006;103:12405–10.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Dong J, Feldmann G, Huang J, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120–33.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Huang J, Wu S, Barrera J, Matthews K, Pan D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell. 2005;122:421–34.PubMedCrossRefGoogle Scholar
  10. 10.
    Edgar BA. From cell structure to transcription: Hippo forges a new path. Cell. 2006;124:267–73.PubMedCrossRefGoogle Scholar
  11. 11.
    Bao Y, Nakagawa K, Yang Z, et al. A cell-based assay to screen stimulators of the Hippo pathway reveals the inhibitory effect of dobutamine on the YAP-dependent gene transcription. J Biochem. 2011;150:199–208.PubMedCrossRefGoogle Scholar
  12. 12.
    Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 2010;10:760–74.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Huang JM, Nagatomo I, Suzuki E, et al. YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14. Oncogene. 2013;32:2220–9.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Kim JM, Kang DW, Long LZ, et al. Differential expression of Yes-associated protein is correlated with expression of cell cycle markers and pathologic TNM staging in non-small-cell lung carcinoma. Hum Pathol. 2011;42:315–23.PubMedCrossRefGoogle Scholar
  15. 15.
    Urtasun R, Latasa MU, Demartis MI, et al. Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/yes-associated protein-mediated activation. Hepatology. 2011;54:2149–58.PubMedCrossRefGoogle Scholar
  16. 16.
    Yoo SB, Kim YJ, Kim H, et al. Alteration of the E-cadherin/β-catenin complex predicts poor response to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment. Ann Surg Oncol. 2013;20(Suppl 3):545–52.CrossRefGoogle Scholar
  17. 17.
    Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th edition. New York: Springer, 2010.Google Scholar
  18. 18.
    Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.PubMedCrossRefGoogle Scholar
  19. 19.
    Steinhardt AA, Gayyed MF, Klein AP, et al. Expression of Yes-associated protein in common solid tumors. Hum Pathol. 2008;39:1582–9.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X. Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci. 2010;101:1279–85.PubMedCrossRefGoogle Scholar
  21. 21.
    Sun PL, Seol H, Lee HJ, et al. High incidence of EGFR mutations in Korean men smokers with no intratumoral heterogeneity of lung adenocarcinomas: correlation with histologic subtypes, EGFR/TTF-1 expressions, and clinical features. J Thorac Oncol. 2012;7:323–30.PubMedCrossRefGoogle Scholar
  22. 22.
    Lee HJ, Xu X, Kim H, et al. Comparison of direct sequencing, PNA clamping-real time polymerase chain reaction, and pyrosequencing methods for the detection of EGFR mutations in non–small cell lung carcinoma and the correlation with clinical responses to EGFR tyrosine kinase inhibitor treatment. Korean J Pathol. 2013;47:52–60.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Kim H, Yoo SB, Choe JY, et al. Detection of ALK gene rearrangement in non–small cell lung cancer: a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression. J Thorac Oncol. 2011;6:1359–66.PubMedCrossRefGoogle Scholar
  24. 24.
    Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244–85.PubMedCrossRefGoogle Scholar
  25. 25.
    Ha SY, Roh MS. The new 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma in resected specimens: clinicopathologic relevance and emerging issues. Korean J Pathol. 2013;47:316–25.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Wang H, Du YC, Zhou XJ, Liu H, Tang SC. The dual functions of YAP-1 to promote and inhibit cell growth in human malignancy. Cancer Metastasis Rev. 2014;33:173–81. Google Scholar
  27. 27.
    Su LL, Ma WX, Yuan JF, Shao Y, Xiao W, Jiang SJ. Expression of Yes-associated protein in non–small cell lung cancer and its relationship with clinical pathological factors. Chin Med J (Engl). 2012;125:4003–8.PubMedGoogle Scholar
  28. 28.
    Xu MZ, Yao TJ, Lee NP, et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer. 2009;115:4576–85.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev. 2001;15:1229–41.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003;11:11–23.PubMedCrossRefGoogle Scholar
  31. 31.
    Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.PubMedCrossRefGoogle Scholar
  32. 32.
    Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500.PubMedCrossRefGoogle Scholar
  33. 33.
    Hirsch FR, Bunn PA Jr. EGFR testing in lung cancer is ready for prime time. Lancet Oncol. 2009;10:432–3.PubMedCrossRefGoogle Scholar
  34. 34.
    Janku F, Stewart DJ, Kurzrock R. Targeted therapy in non-small-cell lung cancer—is it becoming a reality? Nat Rev Clin Oncol. 2010;7:401–14.PubMedCrossRefGoogle Scholar
  35. 35.
    Lackner MR, Wilson TR, Settleman J. Mechanisms of acquired resistance to targeted cancer therapies. Future Oncol. 2012;8:999–1014.PubMedCrossRefGoogle Scholar
  36. 36.
    Okamoto K, Okamoto I, Okamoto W, et al. Role of survivin in EGFR inhibitor–induced apoptosis in non–small cell lung cancers positive for EGFR mutations. Cancer Res. 2010;70:10402–10.PubMedCrossRefGoogle Scholar
  37. 37.
    Ohashi K, Maruvka YE, Michor F, Pao W. Epidermal growth factor receptor tyrosine kinase inhibitor–resistant disease. J Clin Oncol. 2013;31:1070–80.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Nakagawa T, Takeuchi S, Yamada T, et al. Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer. Mol Cancer Ther. 2012;11:2149–57.PubMedCrossRefGoogle Scholar
  39. 39.
    Tabernero J. The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res. 2007;5:203–20.PubMedCrossRefGoogle Scholar
  40. 40.
    Hsu FD, Nielsen TO, Alkushi A, et al. Tissue microarrays are an effective quality assurance tool for diagnostic immunohistochemistry. Mod Pathol. 2002;15:1374–80.PubMedCrossRefGoogle Scholar
  41. 41.
    Voduc D, Kenney C, Nielsen TO. Tissue microarrays in clinical oncology. Semin Radiat Oncol. 2008;18:89–97.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Ping-Li Sun
    • 1
  • Ji Eun Kim
    • 2
  • Seol Bong Yoo
    • 3
  • Hyojin Kim
    • 1
  • Yan Jin
    • 1
  • Sanghoon Jheon
    • 4
  • Kwhanmien Kim
    • 4
  • Choon Taek Lee
    • 5
  • Jin-Haeng Chung
    • 1
  1. 1.Department of Pathology, Seoul National University Bundang HospitalSeoul National University College of MedicineSeongnamRepublic of Korea
  2. 2.Department of Pathology, Seoul National University Boramae HospitalSeoul National University College of Medicine SeoulSeoulRepublic of Korea
  3. 3.Department of PathologyPresbyterian Medical CenterJeonjuRepublic of Korea
  4. 4.Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang HospitalSeoul National University College of MedicineSeongnamRepublic of Korea
  5. 5.Department of Internal MedicineSeoul National University Bundang Hospital, Seoul National University College of MedicineSeongnamRepublic of Korea

Personalised recommendations