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

Walker, Sarah, Wankell, Miriam, White, Rose, Ho, Vikki, Deo, Nikita, Devine, Carol, Dewdney, Brittany, Bhathal, Prithi, Govaere, Olivier, Roskams, Tania, Qiao, Liang, George, Jacob, and Hebbard, Lionel (2019) Targeting mTOR and Src restricts hepatocellular carcinoma growth in a novel murine liver cancer model. PLoS One, 14 (2). e0212860.

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Abstract

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.

Item ID: 57214
Item Type: Article (Research - C1)
ISSN: 1932-6203
Keywords: liver cancer, adiponectin, mtor, src
Copyright Information: Copyright © 2019 Walker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funders: Robert W. Storr Bequest, University of Sydney (US), National Health and Medical Research Council of Australia (NHMRC), Cancer Council NSW (CC), Cancer Council Queensland (CCQ), Belgian Federal Science Policy Office
Projects and Grants: NHMRC 1047417, NHMRC 1006200, NHMRC 1087297, CC 1070076, CC 1069733, CCQ 1123436, Interuniversity Attraction Poles program - P7/83-HEPRO (TR)
Date Deposited: 26 Feb 2019 02:45
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1112 Oncology and Carcinogenesis > 111209 Solid Tumours @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920105 Digestive System Disorders @ 100%
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