Author ORCID Identifier
0009-0001-6443-3820
Date of Graduation
8-2024
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Raghu Kalluri, M.D., Ph.D.
Committee Member
Jian Hu, Ph.D.
Committee Member
Florencia McAllister, M.D.
Committee Member
Shabnam Shalapour, Ph.D.
Committee Member
Natividad Roberto Fuentes, Ph.D.
Abstract
Functional contribution of epithelial to mesenchymal transition program on KRASG12D targeting efficacy in pancreatic cancer
Ana S. Maldonado, BS
Advisory Professor: Raghu Kalluri, M.D., Ph.D.
Pancreatic Ductal Adenocarcinoma (PDAC), a highly aggressive, metastatic, and therapeutically resistant form of pancreatic cancer has been projected to become the second-leading cause of cancer related mortality in the United States. This is driven by its detection difficulty, treatment efficacy, and asymptomatic nature, among other factors. PDAC is driven predominantly by KRASG12D mutations, which are responsible for the initial development of pancreatic intraepithelial neoplasia (Pan-IN) lesions, that are further maintained and progressed until the emergence of PDAC occurs. Various treatment modalities exist, including chemotherapeutics such as gemcitabine, and FOLFIRINOX (fluorouracil, irinotecan, leucovorin, oxaliplatin), although these have been known for their low efficacy. The emergence of KRASG12C inhibitors, Adagrasib and Sotorasib, paved the way for the development of MRTX1133, a KRASG12D inhibitor. Although MRTX1133 improved survival outcomes in pre-clinical resistance to KRASG12D inhibition develops after prolonged treatment. As such, one of the main investigative avenues towards resistance mechanisms, is the epithelial-to-mesenchymal transition (EMT). This cellular process is involved in acquirement of a mesenchymal phenotype, with the concurrent loss of an epithelial one. Important EMT transcription factors such as Zeb1, Snail and Twist, are involved in various mechanisms, including drug resistance. It has been reported that EMT mediates chemotherapeutic and KRASG12C inhibitor resistance, and as such, it is vital to understand the mechanisms surrounding such phenomenon. To address this, we employed genetically engineered mouse models (GEMMs) of PDAC with deletion of the EMT transcription factor (TF) Zeb1 (Zeb1cKO) and orthotopic models with conditional deletion of the EMT TFs Snail and Twist (STcKO) to evaluate the role of EMT transcription factors in the efficacy of MRTX1133. We further probed the efficacy of Kras inhibition and gemcitabine therapy in the 404P KPC STcKO orthotopic model and found that EMT TFs played no role in primary tumor regression and emergence of resistance following MRTX1133 treatment in the GEMMs and the orthotopic models. Interestingly, we found that STcKO PDAC demonstrated enhanced tumor inhibition with a combination of MRTX1133 and gemcitabine therapies. Our data indicates that gemcitabine therapy exposes unique therapeutic vulnerabilities of epithelial phenotype pancreatic cancers to KRAS G12D inhibition and suggest that EMT profiling could help identify PDAC patients that would benefit from combination therapy.
Keywords
PDAC, EMT, KRASG12D, DRUG EFFICACY, GEMCITABINE, MRTX1133, INHIBITORS, GEMM, ORTHOTOPIC MICE, DRUG RESISTANCE