Hsu, D. S., Acharya, C. R., Balakumaran, B. S., Riedel, R. F., Kim, M. K., Stevenson, M., Tuchman, S., Mukherjee, S., Barry, W., Dressman, H. K., Nevins, J. R., Powers, S., Mu, D., Potti, A. (March 2009) Characterizing the developmental pathways TTF-1, NKX2-8, and PAX9 in lung cancer. Proc Natl Acad Sci U S A, 106 (13). pp. 5312-5317. ISSN 0027-8424 (Print)1091-6490 (Electronic)
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Abstract
We investigated the clinical implications of lung developmental transcription factors (TTF-1, NKX2–8, and PAX9) that we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the 3 genes were determined and used to risk stratify a non-small-cell lung cancer (NSCLC) clinical data set consisting of 91 early stage tumors. Coactivation of the and pathways identified a cluster of patients with poor survival, representing ≈20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power. Importantly, the poor prognosis associated with coactivation of and was validated in 2 other independent clinical data sets. Furthermore, lung cancer cell lines showing coactivation of the and pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. This suggests that the cohort of patients with coactivation of and pathways appears to be resistant to standard cisplatin therapy, suggesting the need for alternative therapies in this cohort of high-risk patients.
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