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