Characterizing resistance and sensitivity to targeted therapies in patient-derived models of EGFR mutant lung cancer

Advanced non-small cell lung cancer (NSCLC) continues to be an incurable family of thoracic malignancies that is chronically managed with chemotherapy, targeted therapy, and immunotherapy. While the discovery of driver oncogenes and the advent of targeted therapies in the last decade have vastly improved disease management for patients whose tumors harbor druggable mutations, the clinical efficacy of targeted therapies remains limited by the development of acquired drug resistance. One proto-oncogene that is mutated in 10-15% of NSCLC is the epidermal growth factor receptor (EGFR). Activating EGFR mutations drive constitutive receptor phosphorylation, which in turn activates downstream kinase cascades promoting cell proliferation and survival. Tumors harboring sensitizing EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), before ultimately becoming refractory to therapy. Resistance to targeted EGFR TKIs predominantly occurs through reactivation of EGFR signaling, either by acquisition of secondary EGFR mutations that enable the receptor to evade drug binding and remain active, or through compensatory upregulation of bypass signaling pathways that reactivate canonical EGFR-downstream signaling. MET kinase is a proto-oncogene that is commonly amplified and/or overexpressed and activated in EGFR-driven tumors to confer TKI resistance through bypass signaling. Here, we develop and characterize novel models of drug resistance in EGFR mutant backgrounds in an effort to pinpoint novel therapeutic opportunities for EGFR-driven tumors progressed on first-line therapy with EGFR tyrosine kinase inhibitors. In Chapter 2, CRISPR-Cas9 genome engineering is applied to introduce drug resistance mutations into EGFR in inhibitor-naïve EGFR-dependent cell line models, creating a platform to test novel targeted inhibitors and rational combination therapies. The focus of Chapter 3 is the identification and characterization of a novel subset of EGFR-mutant, MET upregulated lung cancers from patient-derived specimens that exhibit a complete switch away from EGFR addiction to MET oncogene dependency. Finally, in Chapter 4, we observe glucocorticoid associated modulation of drug sensitivity in a subset of NSCLC lines, and examine the biological contexts underlying this glucocorticoid response. Through development and characterization of novel patient-derived models of EGFR-driven NSCLC, we hope to contribute to a deeper understanding of the molecular processes underlying resistance and sensitivity to targeted therapies in NSCLC.