Proteomic profiling identifies pathways dysregulated in non-small cell lung cancer and an inverse association of AMPK and adhesion pathways with recurrence

Meera Nanjundan, Lauren Averett Byers, Mark S. Carey, Doris R. Siwak, Maria Gabriela Raso, Lixia Diao, Jing Wang, Kevin R. Coombes, Jack A. Roth, Gordon B. Mills, Ignacio I. Wistuba, John D. Minna, John V. Heymach

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

The identification of key pathways dysregulated in non-small cell lung cancer (NSCLC) is an important step toward understanding lung pathogenesis and developing new therapeutic approaches. Methods: Toward this goal, reverse-phase protein lysate arrays (RPPA) were used to compare signaling pathways between NSCLC tumors and paired normal lung tissue from 46 patients and assess their association with clinical outcome. Results: After RPPA quantification of 63 proteins and phosphoproteins, tissue pairs were randomized to a training set (n = 25 pairs) and test set (n = 21 pairs). In the training set, 15 protein markers were differentially expressed between tumors and normal lung (p ≤ 0.01), including markers in the PI3K/AKT and p38 MAPK signaling pathways (e.g., p70S6K, S6, p38, and phospho-p38), as well as caveolin-1 and β-catenin. A four-protein signature (p70S6K, cyclin B1, pSrc(Y527), and caveolin-1) independent of histology classified specimens as tumor versus normal with a predicted accuracy of 83%, sensitivity of 67%, and specificity of 100%. The signature was validated in the test set, correctly classifying all normal tissues and 14 of 21 tumor tissues. RPPA results were confirmed by immunohistochemistry for caveolin-1 and p70S6K. In tumors from patients with resected NSCLC, expression of proteins in the energy-sensing AMPK pathway (pLKB1, AMPK, p-Acetyl-CoA, pTSC2), adhesion, EGFR, and Rb signaling pathways was inversely associated with NSCLC recurrence. Conclusions: These data provide evidence for dysregulation of several pathways including those involving energy sensing and adhesion that are potentially associated with NSCLC pathogenesis and disease recurrence.

Original languageEnglish (US)
Pages (from-to)1894-1904
Number of pages11
JournalJournal of Thoracic Oncology
Volume5
Issue number12
DOIs
StatePublished - Dec 2010

Keywords

  • AMPK
  • Adhesion
  • NSCLC
  • Proteomics
  • Recurrence

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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    Nanjundan, M., Byers, L. A., Carey, M. S., Siwak, D. R., Raso, M. G., Diao, L., Wang, J., Coombes, K. R., Roth, J. A., Mills, G. B., Wistuba, I. I., Minna, J. D., & Heymach, J. V. (2010). Proteomic profiling identifies pathways dysregulated in non-small cell lung cancer and an inverse association of AMPK and adhesion pathways with recurrence. Journal of Thoracic Oncology, 5(12), 1894-1904. https://doi.org/10.1097/JTO.0b013e3181f2a266