Abstract 3020: An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development

Abstract

Abstract KRAS and EGFR have been shown to function as essential mediators of pancreatic cancer development. In addition, KRAS and EGFR have been separately shown to interact with and perturb the function of Argonaute 2 (AGO2), a key mediator of RNA-mediated gene silencing. Here, we employed a genetically engineered mouse model of pancreatic cancer to define the effects of conditional loss of AGO2 in KRASG12D driven pancreatic cancer. Genetic ablation of AGO2 does not interfere with development of the normal pancreas or KRASG12D driven early precursor pancreatic intraepithelial (PanIN) lesions. However, AGO2 loss prevents progression from early to late PanIN lesions, development of pancreatic ductal adenocarcinoma (PDAC), and metastatic progression. This results in a dramatic increase in survival of KRASG12D mutant mice deficient in AGO2 expression. In both mouse and human pancreatic tissues, increased AGO2 expression at the plasma membrane is associated with PDAC progression. Mechanistically, within early precursor PanIN lesions, loss of AGO2 elevates phospho-EGFR levels and activates wild-type RAS, antagonizing KRASG12D activation and PDAC development. Furthermore, we observe that phosphorylation of AGO2Y393 by EGFR disrupts the interaction of wild-type RAS with AGO2, but does not affect the interaction of mutant KRAS with AGO2. Taken together, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR and wild-type RAS signaling, and an AGO2-dependent phase wherein the KRAS-AGO2 interaction is critical to the progression from PanIN to PDAC. A recent study by Phillip Sharp and Tyler Jacks describes a requirement for the oncogenic KRAS-AGO2 interaction in the development of a transplant mouse model of plasmablastic lymphoma, and together these studies substantiate the role of the interaction in KRAS oncogenesis. Citation Format: Sunita Shankar, Jean Tien, Ronald F. Siebenaler, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Kristin M. Juckette, Alice Xu, Malay Mody, Andrew Goodrum, Grace Tsaloff, Ingrid J. Apel, Lisha Wang, Javed Siddiqui, Jiaqi Shi, Chandan Kumar-Sinha, Arul Chinnaiyan. An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3020.