Examination Date
Spring 3-19-2026
Degree
Dissertation
Degree Program
Human Genetics
Examination Committee
Bolin Liu, Michael Lan, Krzysztof Reiss, Qiang Shen, Jiri Adamec
Abstract
Lung cancer remains the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) comprises most cases and is frequently driven by KRAS mutations. Previously, KRAS was considered undruggable; however, the discovery of a novel binding pocket led to FDA approval of two KRAS G12C inhibitors. Despite this, their clinical efficacy is limited by low response rates and the development of therapeutic resistance. Drug repurposing represents a promising strategy to address this challenge. Metformin, an anti-type II diabetes medication, has demonstrated potential anticancer effects, including impacts on cell proliferation, metabolism, apoptosis, and signaling. Although our prior studies demonstrated that metformin induces apoptosis in NSCLC cell lines and a xenograft mouse model, the role of KRAS mutation status in determining metformin sensitivity remains unclear. Thus, our central hypothesis is that metformin exhibits potent antitumor activity in KRAS-mutant NSCLC via increased intracellular accumulation driven by differential expression of metformin transporters, leading to metabolic stress and disruption of oncogenic signaling. Furthermore, we hypothesize that metformin synergizes with KRAS G12C inhibitors to enhance therapeutic efficacy by potentiating inhibition of KRAS-dependent signaling pathways and promoting NSCLC cell death.
To test these hypotheses, we performed comprehensive in vitro and in vivo studies comparing KRAS wild-type and mutant NSCLC models. KRAS-mutant cells exhibited greater sensitivity to metformin, associated with increased intracellular accumulation and alterations in signaling, metabolism, and cell cycle regulation (Chapter 2). Combination treatment with metformin and KRAS G12C inhibitors produced greater inhibition of cell growth than single agent treatment and prevented the p-ERK rebound seen with KRAS inhibitor monotherapy (Chapter 3). In xenograft models, combination therapy suppressed tumor growth, reduced proliferation markers and p-ERK expression, and increased cleaved caspase-3 levels (Chapter 3). Collectively, this work provides mechanistic insight into metformin’s antitumor activity and establishes preclinical rationale for combining metformin with KRAS-targeted therapies in NSCLC.
Recommended Citation
Larsen, Margaret E., "Therapeutic Potential of Metformin in KRAS-Mutant Non-Small Cell Lung Cancer" (2026). School of Graduate Studies. 22.
https://digitalscholar.lsuhsc.edu/etd_sgs/22
Dissertation Report Form