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Gastroenterology. 2019 May 4. pii: S0016-5085(19)36771-X. doi: 10.1053/j.gastro.2019.05.001. [Epub ahead of print]

Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response.

Author information

1
Centre de Recherche des Cordeliers, Sorbonne Universités, Inserm, UMRS-1138, F-75006 Paris, France; Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, équipe labellisée Ligue Contre le Cancer, F-75000 Paris, France.
2
Division of Gastroenterology and Hepatology, Clinic of Internal, Medicine III, Medical University of Vienna, Vienna, Austria.
3
Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
4
RPPA platform, Curie Institute, PSL research university, Paris, France.
5
Bariton INSERM, UMR-1053, Bordeaux, France; Department of Pathology, Pellegrin Hospital, Hospital of Bordeaux, Bordeaux, France.
6
Anathomopathology Department, Henri Mondor Hospital, Créteil; University of Paris Est Créteil, Inserm U955, Team 18, Mondor Institute of Biomedical Research, France.
7
Centre de Recherche des Cordeliers, Sorbonne Universités, Inserm, UMRS-1138, F-75006 Paris, France; Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, équipe labellisée Ligue Contre le Cancer, F-75000 Paris, France; Liver unit, Jean Verdier Hospital, University Hospitals Paris-Seine-Saint-Denis, AP-HP, Bondy, France; Training and Research Unit of Health Medicine and Human Biology, University of Paris 13, Community of Universities and Institutions Sorbonne Paris Cité, Paris, France.
8
Centre de Recherche des Cordeliers, Sorbonne Universités, Inserm, UMRS-1138, F-75006 Paris, France; Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, équipe labellisée Ligue Contre le Cancer, F-75000 Paris, France; European Hospital Georges Pompidou, AP-HP, F-75015, Paris, France. Electronic address: jessica.zucman-rossi@inserm.fr.
9
Centre de Recherche des Cordeliers, Sorbonne Universités, Inserm, UMRS-1138, F-75006 Paris, France; Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, équipe labellisée Ligue Contre le Cancer, F-75000 Paris, France. Electronic address: sandra.rebouissou@inserm.fr.

Abstract

BACKGROUND AND AIMS:

Hepatocellular carcinomas (HCCs) are heterogeneous aggressive tumors with low rates of response to treatment at advanced stages. We screened a large panel of liver cancer cell lines (LCCLs) to identify agents that might be effective against HCC and markers of therapeutic response.

METHODS:

We performed whole-exome RNA and microRNA sequencing and quantification of 126 proteins in 34 LCCLs. We screened 31 anti-cancer agents for their ability to decrease cell viability. We compared genetic, RNA, and protein profiles of LCCLs with those of primary HCC samples and searched for markers of response.

RESULTS:

The protein and RNA signatures of the LCCLs were similar to those of the proliferation class of HCC, which is the most aggressive tumor type. Cell lines with alterations in genes encoding members of the Ras-MAPK signaling pathway and that required FGF19 signaling via FGFR4 for survival were more sensitive to trametinib than to FGFR4 inhibitors. Amplification of FGF19 resulted in increased activity of FGF19 only in tumor cells that kept a gene expression pattern of hepatocyte differentiation. We identified single agents and combinations of agents that reduced viability of cells with features of the progenitor subclass of HCC. LCCLs with inactivating mutations in TSC1 and TSC2 were sensitive to the mTOR inhibitor rapamycin, and cells with inactivating mutation in TP53 were sensitive to the AURKA inhibitor alisertib. Amplification of MET was associated with hypersensitivity to cabozantinib and the combination of sorafenib and inhibitors of MEK1 and MEK2 had a synergistic anti-proliferative effect.

CONCLUSION:

LCCLs can be screened for drugs and agents that might be effective for treatment of HCC. We identified genetic alterations and gene expression patterns associated with response to these agents. This information might be used to select patients for clinical trials.

KEYWORDS:

MEK inhibitor; biomarker; liver tumor; response to therapy

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