Oncogenic dependency on β-catenin in liver cancer cell lines correlates with pathway activation
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Zhihu Ding1, Chaomei Shi1, Lan Jiang1, Tatiana Tolstykh1, Hui Cao1, Dinesh S. Bangari2, Susan Ryan2, Mikhail Levit3, Taiguang Jin4, Karl Mamaat1,8, Qunyan Yu1, Hui Qu1, Joern Hopke5, May Cindhuchao5, Dietmar Hoffmann5, Fangxian Sun1, Mike W. Helms6, Kerstin Jahn-Hofmann6, Sabine Scheidler6, Liang Schweizer4,9, Douglas D. Fang7,10, Jack Pollard1, Christopher Winter1 and Dmitri Wiederschain1
1Sanofi Oncology Therapeutic Area, Cambridge, MA, USA
2Sanofi Translational In Vivo Models, Framingham, MA, USA
3Sanofi Translational Sciences, Cambridge, MA, USA
4Sanofi Asia Pacific R&D Hub, Shanghai, People’s Republic of China
5Sanofi Biologics Research/Molecular Screening Technology, Cambridge, MA, USA
6Sanofi Biologics Research/Nucleic Acid Therapeutics, Frankfurt am Main, Germany
7Discovery Services, WuXi AppTec Co., Shanghai, China
8Current address: Leica Biosystems, Boston, MA
9Current address: Harbour BioMed, Shanghai, People’s Republic of China
10Current address: Ascentage Pharma Group, Ltd., Suzhou, People’s Republic of China
Dmitri Wiederschain, email: Dmitri.Wiederschain@sanofi.com
Keywords: hepatocellular carcinoma, β-catenin, cell proliferation, siRNA, phenotypic rescue
Received: August 16, 2017 Accepted: September 13, 2017 Published: September 28, 2017
Hepatocellular carcinoma (HCC) represents a serious public health challenge with few therapeutic options available to cancer patients.Wnt/β-catenin pathway is thought to play a significant role in HCC pathogenesis. In this study, we confirmed high frequency of CTNNB1 (β-catenin) mutations in two independent cohorts of HCC patients and demonstrated significant upregulation of β-catenin protein in the overwhelming majority of HCC patient samples, patient-derived xenografts (PDX) and established cell lines. Using genetic tools validated for target specificity through phenotypic rescue experiments, we went on to investigate oncogenic dependency on β-catenin in an extensive collection of human HCC cells lines. Our results demonstrate that dependency on β-catenin generally tracks with its activation status. HCC cell lines that harbored activating mutations in CTNNB1 or displayed elevated levels of non-phosphorylated (active) β-catenin were significantly more sensitive to β-catenin siRNA treatment than cell lines with wild-type CTNNB1 and lower active β-catenin. Finally, significant therapeutic benefit of β-catenin knock-down was demonstrated in established HCC tumor xenografts using doxycycline-inducible shRNA system. β-catenin downregulation and tumor growth inhibition was associated with reduction in AXIN2, direct transcriptional target of β-catenin, and decreased cancer cell proliferation as measured by Ki67 staining. Taken together, our data highlight fundamental importance of aberrant β-catenin signaling in the maintenance of oncogenic phenotype in HCC.
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