Year: 2025
Type: dissertation
Abstract: Non-small cell lung cancer (NSCLC) accounts for over 1.8 million deaths worldwide each year. One-quarter of the most common form of NSCLC, lung adenocarcinoma (LUAD), possess mutations in the Kirsten rat viral oncogene homolog (KRAS), which drive tumor development and progression. Within the last decade, discoveries related to KRAS have dramatically shifted the once sombre research landscape to one that is exciting, and they have positively improved the treatment options for LUAD patients. Unfortunately, drugs developed via these discoveries remain ineffective in half of the patient population, underscoring a large unmet clinical need for efficacious therapies. To enhance our understanding of this issue, preclinical investigations of these molecules must be performed in models relevant to human cancer, including patient-derived xenografts (PDX) and xenograft-derived organoids (XDO). Using these models to understand the underlying tumor biology upon treatment exposure can guide evaluations of drug resistance and suggest therapeutic methodologies to sensitize tumors to KRAS-targeted agents.In this dissertation, I have utilized numerous PDX models to investigate the feasibility of novel treatment strategies against KRAS-mutant LUAD tumors. In the first study, I identified exportin-1 (XPO1) as a pan-cancer target that may be leveraged in KRAS-mutant LUAD, characterized the antitumor efficacy of an XPO1 inhibitor in this context, and compared this activity to clinically approved targeted agents in PDX models with relevant driver mutations. In the second study, I generated XDOs and evaluated the novel class of GDP-KRASG12C inhibitors in both XDO and PDX models, studied its short-term pharmacodynamic effects on tumor gene expression and protein signaling, and identified mechanisms of intrinsic resistance to these compound as well as methods of overcoming this resistance. In the third study, I simulated the treatment of a patient by administering drug for an extended period and generated an acquired resistance model to a GDP-KRASG12C inhibitor, and investigated putative acquired resistance mechanisms. The findings highlighted in this dissertation provide insight into the underlying mechanisms of drug resistance in the context of KRAS-mutant LUAD and may be used as guidance for the clinical assessment of these molecules.
Source: TSpace (University of Toronto)
Author: Rosen, Joshua Cody
Institution: University of Toronto
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7132995834