Targeting mTOR and Src restricts hepatocellular carcinoma growth in a novel murine liver cancer model

• Published in: PloS one 2019-02, Vol.14 (2), p.e0212860
• Main Authors: Walker, Sarah, Wankell, Miriam, Ho, Vikki, White, Rose, Deo, Nikita, Devine, Carol, Dewdney, Brittany, Bhathal, Prithi, Govaere, Olivier, Roskams, Tania, Qiao, Liang, George, Jacob, Hebbard, Lionel
• Format: Article
• Language: English
• Subjects: Adiponectin; Analysis; Animals; Antimitotic agents; Antineoplastic agents; Biology; Biology and Life Sciences; Cancer; Carcinogens; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - pathology; Cell cycle; Cell Line, Tumor; Combinatorial analysis; Dasatinib - pharmacology; Diethylnitrosamine; Drug Delivery Systems; Genotype & phenotype; Genotypes; Health aspects; Hepatitis; Hepatitis B virus; Hepatocellular carcinoma; Hepatology; Hepatoma; Hospitals; Humans; Inhibitors; Kinases; Liver; Liver cancer; Liver diseases; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - enzymology; Liver Neoplasms, Experimental - pathology; Medical prognosis; Medical research; Medicine; Medicine and Health Sciences; Metabolic syndrome; Metastasis; Mice; Mice, Knockout; Pathology; Prognosis; Protein folding; Proteins; Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors; Proto-Oncogene Proteins pp60(c-src) - metabolism; Rapamycin; Registered nurses; Research and Analysis Methods; Sirolimus - pharmacology; Src protein; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0212860

Liver cancer is a poor prognosis cancer with limited treatment options. To develop a new therapeutic approach, we derived HCC cells from a known model of murine hepatocellular carcinoma (HCC). We treated adiponectin (APN) knock-out mice with the carcinogen diethylnitrosamine, and the resulting tumors were 7-fold larger than wild-type controls. Tumors were disassociated from both genotypes and their growth characteristics evaluated. A52 cells from APN KO mice had the most robust growth in vitro and in vivo, and presented with pathology similar to the parental tumor. All primary tumors and cell lines exhibited activity of the mammalian target of Rapamycin (mTOR) and Src pathways. Subsequent combinatorial treatment, with the mTOR inhibitor Rapamycin and the Src inhibitor Dasatinib reduced A52 HCC growth 29-fold in vivo. Through protein and histological analyzes we observed activation of these pathways in human HCC, suggesting that targeting both mTOR and Src may be a novel approach for the treatment of HCC.