A Pharmacogenomic Landscape in Human Liver Cancers

Cancer Cell. 2019 Aug 12;36(2):179-193.e11. doi: 10.1016/j.ccell.2019.07.001. Epub 2019 Aug 1.

Abstract

Liver cancers are highly heterogeneous with poor prognosis and drug response. A better understanding between genetic alterations and drug responses would facilitate precision treatment for liver cancers. To characterize the landscape of pharmacogenomic interactions in liver cancers, we developed a protocol to establish human liver cancer cell models at a success rate of around 50% and generated the Liver Cancer Model Repository (LIMORE) with 81 cell models. LIMORE represented genomic and transcriptomic heterogeneity of primary cancers. Interrogation of the pharmacogenomic landscape of LIMORE discovered unexplored gene-drug associations, including synthetic lethalities to prevalent alterations in liver cancers. Moreover, predictive biomarker candidates were suggested for the selection of sorafenib-responding patients. LIMORE provides a rich resource facilitating drug discovery in liver cancers.

Keywords: liver cancer; patient-derived cancer models; pharmacogenomics; sorafenib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Asian Continental Ancestry Group / genetics
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / ethnology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Clinical Decision-Making
  • Databases, Genetic
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / ethnology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Patient Selection
  • Pharmacogenomic Testing
  • Pharmacogenomic Variants*
  • Phenotype
  • Precision Medicine
  • Protein Kinase Inhibitors / pharmacology*
  • Sorafenib / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • Sorafenib