Characterizing the non-genetic mechanisms of EGFR-TKI tolerance and resistance in lung adenocarcinoma

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths in the world. While effective targeted therapies are available for the treatment of epidermal growth factor receptor (EGFR) driven lung adenocarcinoma (LUAD), resistance to these therapies remains a major hurdle to effective patient care. In particular, non-genetic mechanisms of EGFR inhibitor resistance are poorly understood. The progression towards non-genetic mechanisms of EGFR inhibitor resistance are known to involve an intermediate, transitory drug-tolerant persister (DTP) state. In this thesis, I studied two non-genetic mechanisms of therapy resistance to EGFR inhibition: 1) epithelial-mesenchymal transition (EMT) and 2) small cell transformation (SCT). In the first part, I used an integrative approach to characterize an ILK-SFK-YAP molecular mechanism that underlies DTP survival in the progression towards EMT-mediated EGFR inhibitor resistance. In the second part, I described our progressive steps in creating an in vitro model of SCT. At the end of this part, we developed an in vitro LUAD DTP-like model that was induced to express multiple small cell lung cancer markers, clarifying the molecular pathways involved with neuroendocrine transdifferentiation. Overall, this thesis characterizes the molecular alterations that drive two non-genetic mechanisms of EGFR inhibitor resistance, furthering our understanding of how treatment-sensitive LUAD cells can transform into a drug-resistant state.