MODELING EPITHELIAL-MESENCHYMAL TRANSITION-INDUCED ERLOTINIB RESISTANCE IN NON-SMALL CELL LUNG CANCER

Lung cancer is the most common cause of cancer mortality throughout the world with an overall survival rate of around 17%. Adenocarcinoma is the most common histologic subtype of lung cancer, and a majority of human lung adenocarcinomas have somatic mutations in genes encoding members of the EGFR/KRAS/BRAF signaling pathway. Combining this knowledge with animal models of the pathway indicate that this signaling axis is of central importance to lung adenocarcinoma development. Non-small cell lung cancers with EGFR mutations, while initially responding well to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, develop acquired resistance within 10-16 months. A relatively uncharacterized mechanism of resistance is lung cancer cells that have undergone a morphological change, termed epithelial-mesenchymal transition (EMT). Twist1 is one of the inducers of EMT and we have created a transgenic autochthonous lung cancer mouse model expressing EGFRL858R/Twist1. Using this novel in vivo model, as well as in vitro models, we have shown that overexpression of Twist1 can confer resistance to erlotinib in EGFR mutant lung cancers. Using these novel model systems we are trying to determine the downstream effects of Twist1 overexpression that lead to erlotinib resistance. To complement our work on Twist1-mediated erlotinib resistance, a bioinformatic-chemical screen was performed to identify potential pharmacological inhibitors of Twist1. From that screen, a promising class of agents, harmala alkaloids, was identified. Using human lung cancer cell lines to validate these agents has shown that several of the compounds have growth inhibitory effects. We tested one of the most promising compounds, harmine, in vivo with a transgenic KrasG12D/Twist1 mouse model of autochthonous lung adenocarcinomas. When mice were treated with harmine, tumor growth delay was observed by computed tomography imaging in harmine versus vehicle control mice. We are currently in the process of examining the molecular and cellular mechanisms of action of harmine using novel in vitro and in vivo model systems. These results are promising and provide a foundation for future experiments to determine if harmine, by inhibiting Twist1, can re-sensitize EGFR mutant lung cancers to erlotinib