Abstract 5986: Deletion of AKT1 inhibits PTEN-loss induced intrahepatic cholangiocarcinoma but not hepatocellular carcinoma development in mice

Abstract Liver cancer is the third most common cause of cancer-related mortality worldwide, with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) representing the two most common subtypes. Mice lacking the tumor suppressor PTEN in the liver (PtenloxP/loxP; albumin [Alb]-Cre-/+; LiPten) display gradual, age-dependent development of hepatosteatosis and combined HCC-ICC. Pten loss results in activation of the serine/threonine kinase AKT. Of the three AKT isoforms identified to date, AKT1 isoform is implicated in regulation of cell growth, proliferation, and survival. In the present study, we investigated the role of AKT1 in mediating PTEN-loss induced liver cancer development by generating a novel double knockout mouse model (PtenloxP/loxP; Akt1loxP/loxP; Alb-Cre-/+; LiPtenA1). Compared to 6-month-old control animals (Alb-Cre-/-), LiPten mice fed normal chow developed marked hepatomegaly and diffuse steatosis. Loss of AKT1 in LiPten animals was unable to reverse steatosis, and LiPtenA1 animals did not exhibit any differences in body or liver weights. At 12 months old, LiPten mice developed tumor nodules on their livers, with microscopic features of steatosis, ductal proliferation and ectasia, HCC, and ICC. Like LiPten mice, all LiPtenA1 animals developed tumor nodules by 12 months of age. Microscopically, livers of LiPtenA1 mice displayed features of fatty nodules and HCC. Our preliminary analysis of expression of ICC-related genes and immunohistochemical staining of livers for ICC markers revealed significant reduction of ICC phenotype in LiPtenA1 mice. The induced phenotypic switch from combined HCC-ICC in LiPten mice to predominantly HCC in LiPtenA1 mice suggests a role for AKT1 in ICC development and contributes to the understanding of the role of AKT isoforms in regulating liver tumorigenesis. Citation Format: Ielyzaveta Slarve, Yining Ding, Yushan Wang, Zifei Xu, Lina He, Bangyan L. Stiles. Deletion of AKT1 inhibits PTEN-loss induced intrahepatic cholangiocarcinoma but not hepatocellular carcinoma development in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5986.