Keywords
Lung cancer, KRAS, AMG 510, Aquaporin 4, Drug resistance
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. One of the most common genetic aberrations in lung cancer patients is Kirsten rat sarcoma viral oncogene homolog (KRAS). The KRAS protein is a Ras superfamily GTPase that switches between an active GTP-bound form and an inactive GDP-bound form. The consequence of KRAS mutations results in constitutively active downstream pathways involved in uncontrolled cell proliferation and survival. Fortunately, there has been a recent development of KRASG12C inhibitors that directly target mutant KRAS, thereby arresting its proliferative effects. A recently FDA-approved KRASG12C inhibitor for the treatment of non-small cell lung cancer, Sotorasib (AMG 510), has been shown to produce insubstantial clinical response rates and a short duration of response. Similar to other targeted therapies, the limitations of this treatment are primarily due to the emergence of drug resistance. Drug resistance has been studied extensively regarding other anticancer treatments; however, the underlying molecular mechanisms remain poorly characterized. Our investigation begins by establishing and analyzing a subpopulation of cancer cells that evolve and mediate drug resistance, known as drug-tolerant persister cells (DTPCs), in KRASG12C mutant cells using AMG 510. First, we observed the reactivation of a pro-proliferative kinase, ERK, in AMG 510 DTPCs. Additionally, whole transcriptomics analysis, RT-qPCR, and immunofluorescent staining demonstrated significant upregulation of AQP4 in AMG 510 DTPCs compared to drug sensitive cells (DSCs). Aquaporin 4 (AQP4) is a water-selective transmembrane protein that regulates fluid homeostasis in many organ systems, including the lungs, and is involved in intracellular calcium signaling. We aim to explore the connections between AQP4, ERK, and calcium signaling in promoting drug tolerance to AMG 510. The insights gained from this research could lead to improved targeted therapies and clinical outcomes by identifying AQP4 as a resistance-driving biomarker.
Completion Date
2024
Semester
Spring
Committee Chair
Zhang, Wencai
Degree
Master of Science (M.S.)
College
College of Medicine
Department
Biomedical Sciences
Degree Program
Biotechnology
Format
application/pdf
Identifier
DP0028300
URL
https://purls.library.ucf.edu/go/DP0028300
Language
English
Rights
In copyright
Release Date
May 2029
Length of Campus-only Access
5 years
Access Status
Masters Thesis (Campus-only Access)
STARS Citation
Luna, Nastassja G., "Aquaporin 4 promotes Drug Tolerance to AMG 510 in KRASG12C mutant Non-Small Cell Lung Cancer" (2024). Graduate Thesis and Dissertation 2023-2024. 131.
https://stars.library.ucf.edu/etd2023/131
Accessibility Status
Meets minimum standards for ETDs/HUTs
Restricted to the UCF community until May 2029; it will then be open access.