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.

Duke Scholars

Author Richard Francis Riedel Medicine, Medical Oncology