Abstract 1790: Investigation of oncogenic G-protein coupled receptor signaling pathways in <i>Kras</i> dependent pancreatic cancer cell lines
Authors: Ozhan Ocal, Raymond MacDonald, Rolf A. Brekken, Thomas Wilkie
Journal: Cancer Research (2019)

Abstract Pancreatic Ductal Adenocarcinoma (PDA) is the most common form of pancreatic cancer driven primarily by mutations in V-Ki-Ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (Kras) gene. Its most common mutation, G12D, cause KRAS to remain constitutively active. KrasG12D expressing pancreatic acinar cells undergo transdifferentiation into ductal phenotype and form early tumorigenic lesions called Pancreatic Intraepithelial Neoplasm (PanIN). Coincidentally occurring inactivating mutations of tumor suppressor genes, such as Cyclin-dependent Kinase Inhibitor 2A (Cdkn2a), Tumor Protein p53 (Tp53), and Mothers Against Decapentaplegic Homolog 4 (Smad4) trigger progression of PanINs through stages from 1A to 3, eventually leading to carcinoma in situ and metastasis. G-protein Coupled Receptors (GPCR) are transmembrane receptors that transfer extracellular signals to intracellular heterotrimeric G-proteins with Gα and Gβγ subunits. Upon activation, dissociated Gα and Gβγ subunits separately induce intracellular second messengers for key cellular responses involved in various aspects of development, metabolism, and cell motility. GPCR signaling is negatively regulated by intracellular Regulator of G-protein Signaling (RGS) proteins that deactivate G-protein by mediating re-association of Gα and Gβγ subunits. Although GPCRs are the largest non-antibiotic drug targets, their specific role in pancreatic cancer is not much known. GPCR signaling can influence RTK pathways in cross-talk via various second messengers. The interplay between these two major classes of cellular pathways employing both heterotrimeric and monomeric G-proteins has therefore potential to shed new light on pancreatic cancer research. We have previously identified Rgs16 expression as a marker of pancreatic tumor formation in Rgs16::GFP o/o; Ptf1aCre/+; Lox-STOP-Lox-KrasG12D/+; Cdkn2af/f (Rgs16::GFP-KIC) mice from the onset of earliest PanINs at two weeks of age (Dis. Model Mech. 8, 1201). Using ImageJ software to quantitatively determine eGFP expression in micrographs, we have developed a rapid in vivo assay (RIVA) where we represent pancreatic tumor burden by one month of age and compare outcomes of known and novel therapeutics following two week long drug regimens. We found that just like the recently developed drug, BGB324, targeting an important RTK, called Anexelekto (Axl), the anticoagulant warfarin was more effective in reducing tumor burden than standard chemotherapy alone. Currently, my research focus is centered on understanding active GPCR pathways that stimulate cell growth, survival, and migration by enhancement of Kras downstream signaling. My aim is comparison of the effects of general G-protein signaling inhibition in Kras mutant and wild-type cell lines, such as AsPC-1 in contrast to BxPC-3, on cell behavior and making connections to active GPCR signaling components. Citation Format: Ozhan Ocal, Raymond MacDonald, Rolf A. Brekken, Thomas Wilkie. Investigation of oncogenic G-protein coupled receptor signaling pathways in Kras dependent pancreatic cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1790.