Preclinical Modeling of Driver Alterations in Non-small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer related mortality and accounts for more than 1.6 million deaths worldwide each year. In the past decade, therapeutic treatments for NSCLC have extended beyond surgery and standard chemotherapies. These advancements have largely focused on the identification of oncogenic drivers and assessment of their ability to predict response to targeted therapy. Despite these advancements, the lack of initial response to single agent treatment and acquired drug resistance are recurring issues that arise in NSCLC. Additionally, preclinical models such as cell lines have been widely used for drug testing and understanding disease pathogenesis. However, they have molecularly deviated from patient tumors and may not accurately reflect drug response in patients. Thus, there is an unmet need to develop clinically and biologically relevant models of NSCLC. These models may then be used to identify new therapeutic strategies to overcome acquired resistance and improve single agent therapy response with combination therapy targeting the major drivers of this disease. In this dissertation, I have modeled several oncogenic drivers of NSCLC to identify novel treatment strategies using patient-derived xenografts (PDX) and organoids. In the first study, I have determined absence of ALK protein by IHC as a primary resistance mechanism and MET amplification and BRAF mutation as secondary resistance mechanisms to ALK inhibitors in lung adenocarcinoma. In the second study, I have identified CDK4/6 inhibitors as promising agents to use in combination with PI3K inhibitors in PIK3CA mutant lung squamous cell carcinoma (LUSC). In the third study, I have developed a protocol for culturing NSCLC organoids and identified FGFR1 and MEK inhibitor combination as a potential therapeutic strategy in FGFR1 amplified LUSC. The findings outlined in this dissertation will not only describe additional preclinical models, but also therapeutic approaches to overcome acquired drug resistance and improve response to single agent therapy with potential drug combinations in NSCLC.Ph.D