Graduation Date

Spring 5-7-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Kay-Uwe Wagner

Abstract

Pancreatic cancer is a lethal disease that is almost invariably associated with a KRAS gene mutation. Due to a very high frequency of gain-of-function mutations within the KRAS gene, and its proven role in initiation of pancreatic cancer in animal models, mutant KRAS is considered a rational therapeutic target. To determine the potential role of oncogenic KRAS in pancreatic tumor maintenance in vivo, we generated a mouse model with a Doxycycline regulated expression of oncogenic KRAS (KRASG12D) in pancreas. Using this reversible model, we demonstrated that the expression of oncogenic KRAS in a Cdkn2a deficient background was sufficient to induce invasive pancreatic cancer with distant metastasis that regressed completely upon ablation of oncogenic KRAS in both primary and tumor-transplanted recipient mice. This finding suggests that the expression of oncogenic KRAS is required for the maintenance of pancreatic cancer, and provides a strong rationale for targeting KRAS in the treatment of pancreatic cancer.

Despite the complete macroscopic remission of invasive tumors upon downregulation of oncogenic KRAS, a few cancer cells survived and remained dormant for a protracted period of time. These cells were responsible for the rapid recurrence upon KRAS reactivation. Genome-wide transcriptome analysis of in vivo-derived bulk and residual cancer cells lacking expression of oncogenic KRAS identified an increase in autocrine IGF-1/AKT signaling in residual cancer cells. Pharmacological inhibition of IGF-1R signaling significantly delayed the tumor burden and recurrence, suggesting a crucial role of IGF-1R signaling in the survival of cancer cells in the absence of oncogenic drivers. Collective results from our study suggest that residual cancer cells can survive in the absence of tumor driving oncogenes by an upregulation of the autocrine IGF1 signaling loop. Co-targeting oncogenic drivers and IGF-1R signaling might be an effective strategy for eliminating minimal residual disease in pancreatic cancer.

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