Genomic profiling of cell lines for personalized targeted therapy for hepatocellular carcinoma

Authors

  • Manjeet Deshmukh PhD,

    1. Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
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  • Yujin Hoshida MD, PhD

    1. Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
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  • Potential conflict of interest: Nothing to report.

To the Editor:

Although a cancer cell line has limitations in modeling the physiological complexity in human cancer, it has shown to be useful as a convenient tool to interrogate the molecular mechanism of action of cancer therapeutics.[1] Finn et al.[2] tested an intriguing idea to use a human hepatocellular carcinoma (HCC) gene signature to probe genomic profiles of hepatoma cell lines to evaluate sensitivity to a molecular targeted agent, dasatinib, although more work is needed to determine its mechanism of action. The authors identified two groups of cell lines according to the presence of a gene signature of “progenitor/HB” subtype linked to a distinct median inhibitory concentration (IC50) profile as well as cell cycle arrest and apoptosis induced by dasatinib. Of note, the classification looks concordant with positivity of alpha-fetoprotein (AFP), which has been repeatedly reported as the major determinant of global transcriptome landscape in hepatoma cells.[3, 4]

We previously annotated the AFP-based subtypes of hepatoma cell lines with various molecular features and clinical phenotypes by using the gene signature assessment.[5, 6] In the analysis, AFP-negative cells, corresponding “S1” subclass identified in our meta-analysis of human HCC cohorts, were characterized by activation of transforming growth factor beta (TGF-β) and Met pathways, suppression of the p53 pathway, overexpression of canonical Wnt pathway target genes, more disseminative phenotype, and in fact enrichment of the “progenitor/HB” signature. These may represent clues to the mechanism. In addition, these findings may collectively suggest that AFP is a predictive biomarker of dasatinib sensitivity. If this is confirmed and the drug shows a clinically meaningful effect in the subset of patients with non-AFP-producing HCC, this could have huge implications in the personalized HCC treatment because AFP is already available in clinics worldwide.

  • Manjeet Deshmukh, Ph.D.Yujin Hoshida, M.D., Ph.D.

  • Liver Cancer Program, Tisch Cancer Institute Division of Liver Diseases, Department of Medicine Icahn School of Medicine at Mount SinaiNew York, NY

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