Functional contribution of epithelial to mesenchymal transition program on KRASG12D targeting efficacy in pancreatic cancer

<p><strong>Functional contribution of epithelial to mesenchymal transition program on KRAS^G12D targeting efficacy in pancreatic cancer</strong></p> <p>Ana S. Maldonado, BS</p> <p>Advisory Professor: Raghu Kalluri, M.D., Ph.D. </p> <p>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 KRAS^G12Dmutations, 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 KRAS^G12Cinhibitors, Adagrasib and Sotorasib, paved the way for the development of MRTX1133, a KRAS^G12Dinhibitor. Although MRTX1133 improved survival outcomes in pre-clinical resistance to KRAS^G12D 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 KRAS^G12C 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) <em>Zeb1</em> (Zeb1^cKO) and orthotopic models with conditional deletion of the EMT TFs <em>Snail</em> and <em>Twist</em> (ST^cKO) 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 ST^cKO 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 ST^cKO 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.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2024

Authors dc:creator

• Maldonado, Ana S
• <p>0009-0001-6443-3820</p>

Contributors dc:contributor

• Raghu Kalluri, M.D., Ph.D.
• Jian Hu, Ph.D.
• Florencia McAllister, M.D.

• PDAC
• EMT
• KRASG12D
• DRUG EFFICACY
• GEMCITABINE
• MRTX1133
• INHIBITORS
• GEMM
• ORTHOTOPIC MICE
• DRUG RESISTANCE
• Cancer Biology
• Therapeutics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1387

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2444