Potential conflict of interest: Nothing to report.
Genomic profiling of cell lines for personalized targeted therapy for hepatocellular carcinoma
Article first published online: 10 OCT 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 6, page 2207, December 2013
How to Cite
Deshmukh, M. and Hoshida, Y. (2013), Genomic profiling of cell lines for personalized targeted therapy for hepatocellular carcinoma. Hepatology, 58: 2207. doi: 10.1002/hep.26407
- Issue published online: 26 NOV 2013
- Article first published online: 10 OCT 2013
- Accepted manuscript online: 20 MAR 2013 04:14PM EST
- Manuscript Accepted: 20 FEB 2013
- Manuscript Received: 19 FEB 2013
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. Finn et al. 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