Author ORCID Identifier

0000-0002-1158-0608

Date of Graduation

8-2017

Document Type

Dissertation (PhD)

Program Affiliation

Biomedical Sciences

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Craig Logsdon, Ph.D.

Committee Member

Bill Mattox, Ph.D.

Committee Member

Candelaria Gomez-Manzano, MD.

Committee Member

Rebecca Berdeaux, Ph.D.

Committee Member

Ralf Krahe, Ph.D.

Abstract

Oncogenic KRAS is central to several cancer types including pancreatic ductal adenocarcinoma (PDAC), but has been determined to be “undruggable”. Recent studies have indicated that oncogenic KRAS is not constitutively active but relies on a feed-forward stimulatory mechanism involving inflammation. In the current study we investigated the mechanisms by which, the receptor for advanced glycation end products (RAGE) affects and maintains KRAS activity. We observed that RAGE levels were elevated and there was a shift in the levels of specific isoforms upon inflammation in pancreatic cells and PDAC. Furthermore, RAGE agonists were found to increase Ras activity and downstream signaling in a time- and dose-dependent manner. Likewise, inhibition of RAGE decreased Ras signaling activity and downstream signals in multiple PDAC cell lines. In vivo, inhibition of RAGE activity using an antagonist inhibited tumor progression and increased survival rate. These data indicate that RAGE plays a central role in maintaining the activity of oncogenic KRAS and supporting tumor growth. These data raises the possibility of new approaches to inhibit the carcinogenic actions of KRAS indirectly by blocking the mechanisms through which, RAGE maintains its activity.

Keywords

RAGE, Erk, NF-kB, PanIN, PDAC, KRas

Available for download on Tuesday, August 14, 2018

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