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

Lookup NU author(s): Dr Olivier Govaere

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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. 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.


Publication metadata

Author(s): Walker S, Wankell M, Ho V, White R, Deo N, Devine C, Dewdney B, Bhathal P, Govaere O, Roskams T, Qiao L, George J, Hebbard L

Publication type: Article

Publication status: Published

Journal: PLoS ONE

Year: 2019

Volume: 14

Issue: 2

Online publication date: 22/02/2019

Acceptance date: 12/02/2019

Date deposited: 11/03/2019

ISSN (electronic): 1932-6203

Publisher: Public Library of Science

URL: https://doi.org/10.1371/journal.pone.0212860

DOI: 10.1371/journal.pone.0212860

PubMed id: 30794695


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