Oncotarget

Research Papers:

Oncogenic dependency on β-catenin in liver cancer cell lines correlates with pathway activation

Zhihu Ding, Chaomei Shi, Lan Jiang, Tatiana Tolstykh, Hui Cao, Dinesh S. Bangari, Susan Ryan, Mikhail Levit, Taiguang Jin, Karl Mamaat, Qunyan Yu, Hui Qu, Joern Hopke, May Cindhuchao, Dietmar Hoffmann, Fangxian Sun, Mike W. Helms, Kerstin Jahn-Hofmann, Sabine Scheidler, Liang Schweizer, Douglas D. Fang, Jack Pollard, Christopher Winter and Dmitri Wiederschain _

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Oncotarget. 2017; 8:114526-114539. https://doi.org/10.18632/oncotarget.21298

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Abstract

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

Correspondence to:

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

ABSTRACT

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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