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.
Subject(s)
Antineoplastic Agents/pharmacology , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Pharmacogenomic Variants , Protein Kinase Inhibitors/pharmacology , Sorafenib/pharmacology , Animals , Asian People/genetics , Carcinoma, Hepatocellular/ethnology , 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/ethnology , Liver Neoplasms/pathology , Male , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Patient Selection , Pharmacogenomic Testing , Phenotype , Precision Medicine , Xenograft Model Antitumor AssaysABSTRACT
Hepatocellular carcinoma (HCC) cell lines are useful in vitro models for the study of primary HCCs. Because cell lines acquire additional mutations in culture, it is important to understand to what extent HCC cell lines retain the genetic landscapes of primary HCCs. Most HCC cell lines were established during the last century, precluding comparison between cell lines and primary cancers. In this study, 9 Chinese HCC cell lines with matched patient-derived cells at low passages (PDCs) were established in the defined culture condition. Whole genome analyses of 4 HCC cell lines showed that genomic mutation landscapes, including mutations, copy number alterations (CNAs) and HBV integrations, were highly stable during cell line establishment. Importantly, genetic alterations in cancer drivers and druggable genes were reserved in cell lines. HCC cell lines also retained gene expression patterns of primary HCCs during in vitro culture. Finally, sequential analysis of HCC cell lines and PDCs at different passages revealed their comparable and stable genomic and transcriptomic levels if maintained within proper passages. These results show that HCC cell lines largely retain the genomic and transcriptomic landscapes of primary HCCs, thus laying the rationale for testing HCC cell lines as preclinical models in precision medicine.
