p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-07, Vol.116 (29), p.14724-14733
• Main Authors: Torres, Carolina, Mancinelli, Georgina, Cordoba-Chacon, Jose, Viswakarma, Navin, Castellanos, Karla, Grimaldo, Sam, Kumar, Sandeep, Principe, Daniel, Dorman, Matthew J., McKinney, Ronald, Hirsch, Emilio, Dawson, David, Munshi, Hidayatullah G., Rana, Ajay, Grippo, Paul J.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Ablation; Activation; Adenocarcinoma; AKT protein; Animals; Antimetabolites, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - therapeutic use; Biological Sciences; Carcinogenesis; Carcinogenesis - drug effects; Carcinogenesis - genetics; Carcinogens; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Class Ia Phosphatidylinositol 3-Kinase - genetics; Class Ib Phosphatidylinositol 3-Kinase - genetics; Class Ib Phosphatidylinositol 3-Kinase - metabolism; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Diet; Diet, High-Fat - adverse effects; Disease Models, Animal; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Fatty Acids, Omega-6 - adverse effects; Female; Gemcitabine; Glucose - metabolism; Hepatotoxicity; High fat diet; Humans; Isoforms; Lipid Metabolism; Liver; Liver - pathology; Male; Mice, Knockout; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Obesity; Obesity - complications; Obesity - etiology; Obesity - metabolism; Pancreas; Pancreas - pathology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Phosphoinositide-3 Kinase Inhibitors - therapeutic use; PNAS Plus; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; Solid tumors; Tumor cells; Tumorigenesis; Tumors; Up-Regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1813012116

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor survival and resistance to conventional therapies. PI3K signaling is implicated in both disease initiation and progression, and specific inhibitors of selected PI3K p110 isoforms for managing solid tumors are emerging. We demonstrate that increased activation of PI3K signals cooperates with oncogenic Kras to promote aggressive PDAC in vivo. The p110γ isoform is overexpressed in tumor tissue and promotes carcinogenesis via canonical AKT signaling. Its selective blockade sensitizes tumor cells to gemcitabine in vitro, and genetic ablation of p110γ protects against Kras-induced tumorigenesis. Diet/obesity was identified as a crucial means of p110 subunit up-regulation, and in the setting of a high-fat diet, p110γ ablation failed to protect against tumor development, showing increased activation of pAKT and hepatic damage. These observations suggest that a careful and judicious approach should be considered when targeting p110γ for therapy, particularly in obese patients.