Use of co-activation of lung cancer specific developmental pathway genes, TTF-1, NKX2-8, and PAX9, to predict prognosis and guide therapeutic strategies.
7511 Background: We recently described a novel, recurring amplicon (14q13.3) specific to NSCLC that harbors three genes, TTF- 1, NKX2-8, and PAX9, important in lung development (Kendall et al. PNAS 2007). METHODS: Using stable transfectants of human bronchial epithelial cells, gene expression profiles representing activation of the biological pathways defined by TTF-1, NKX2-8, and PAX9 were created. Using samples from patients with early stage NSCLC (n=306) and advanced stage (n=41), the clinical relevance of these developmental genes in NSCLC initiation, progression and response to therapy was evaluated. RESULTS: In an initial discovery dataset of patients with early stage NSCLC (n=91), we observed that individual activation of TTF-1, NKX2-8 and PAX9 was not prognostic; however, co- activation of TTF-1 and NKX2-8 pathways identified a cluster of patients representing approximately 20% of patients with poor survival (p=0.01). Using an independent validation set (n=215, 133 squamous and 84 adenocarcinomas), the prognostic validity of TTF-1/NKX2-8 co-activation was further confirmed. Additionally, the independent (of age, gender, pathologic stage, tumor size, and histology) prognostic value of TTF- 1/NKX2-8 co-activation was verified in multivariate analyses (p=0.03). Using in vitro studies involving more than 40 lung cancer cell lines, we demonstrate that TTF-1/NKX2-8 co-activation also predicts resistance to cisplatin, the standard of care for patients with NSCLC. Further in vitro experiments demonstrated the ability of a RAS pathway specific therapy (farnesyl thiosalicyclic acid) to inhibit tumor cell growth in TTF-1/NKX-2 activated cells (p=0.01), suggesting that modulation of the RAS pathway is a rational therapeutic strategy in high risk NSCLC patients with co- activation of specific lung developmental pathways. CONCLUSIONS: Genes critical to lung development, TTF-1, NKX2-8, and PAX9, play a key role in the pathogenesis of NSCLC. Furthermore, knowledge of the activation status of developmental genes specific to lung cancer identifies patients with poor prognosis and provides a novel approach to targeted therapeutics in the adjuvant setting by guiding the appropriate use of RAS pathway specific inhibitors. No significant financial relationships to disclose.
Hsu, SD; Acharya, CR; Riedel, RF; Redman, RC; Garman, KS; Dressman, HK; Ginsburg, G; Powers, S; Mu, D; Potti, A
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