Abstract 4988: PI3Kγ-deficiency protects against pancreatic tumorigenesis at the expense of diet-Induced hyperlipidemia and hepatotoxicity

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) presents a significant challenge clinically, with poor overall survival and widespread resistance to conventional therapies. Several novel molecular targets are being considered in the management of PDAC patients. To this end, as hyperactive PI3K signaling is implicated in both disease incidence and progression, the inhibition of PI3K p110γ isoform is showing early promise in vivo and has been proposed as a reasonable target for therapy. Classically, p110γ is expressed predominantly in macrophages. However, using both primary pancreatic cancer samples and established patient databases, we found that p110γ is commonly upregulated in the cancer epithelium. Further, p110γ is expressed in human cell lines, and the pharmacologic inhibition of p110γ with AS-604850 both delayed mtKRAS/mtTP53-induced acinar-to-ductal metaplasia ex vivo, and sensitized tumor cells to gemcitabine in vitro. Given the apparent importance of epithelial p110γ to the neoplastic phenotype, we next generated mice with constitutive activation of p110γ targeted to the exocrine pancreas (PI3KγCA). When combined with a KRAS activating mutation, PI3KγCA mice developed highly advanced disease forms with robust fibrosis, inflammation, and AKT activation/proliferation. In accordance with these observations, both homo- and heterozygous global deletion of p110γ protected against KRAS-induced tumorigenesis, reducing downstream AKT signaling and proliferation in vivo. However, despite the reduction in tumor burden, mutant KRAS mice with p110γ-deficiency displayed early signs of hepatotoxicity. Since p110γ has several key roles in lipid metabolism, we next assessed p110γ loss in the setting of a high-fat diet (HFD). These mtKRAS/p110γKO mice developed pronounced hyperlipidemia and severe hepatic cell injury/steatosis. Additionally, the previously observed protective effect in the pancreas was markedly diminished, and neoplastic tissues displayed pronounced AKT pathway activation, indicating potential compensatory signaling through non-p110γ isoforms. Indeed, how p110γ loss and lipid accumulation in liver impact development of mtKRAS-induced neoplasia and cancer is a very interesting future aim. Combined, these observations suggest that systemic p110γ inhibition should be carefully considered, particularly given the potential for reduced efficacy, hyperlipidemia, and hepatic injury in obese patients, unless specific targeting to the pancreas can be achieved. Citation Format: Carolina Torres, Daniel R. Principe, Alex Park, Ronald McKinney, Matthew J. Dorman, Ajay Rana, Emilio Hirsch, Jose Cordoba-Chacon, Paul J. Grippo. PI3Kγ-deficiency protects against pancreatic tumorigenesis at the expense of diet-Induced hyperlipidemia and hepatotoxicity [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 4988.