Pharmacogenetics of hepatocellular carcinoma and cholangiocarcinoma

Abstract

Primary liver cancers constitute the fourth most deadly group of cancers. Their poor prognosis is due in part to the pre-existence and/or development, often during treatment, of powerful mechanisms accounting for the poor response of cancer cells to antitumor drugs. These include both impaired gene expression and the appearance of spliced variants, polymorphisms and mutations, affecting the function of genes leading to the reduction in intracellular concentrations of active agents, changes in molecular targets and survival pathways, altered tumor microenvironment and phenotypic transition. The present review summarizes available information regarding the role of germline and somatic mutations affecting drug transporters, enzymes involved in drug metabolism, organelles and signaling molecules related to liver cancer chemoresistance. A more complete picture of the actual complexity of this problem is urgently needed for carrying out further pharmacogenomic studies aimed to improve the management of patients suffering from hepatocellular carcinoma or cholangiocarcinoma.

“Pharmacogenetics of Cancer” - Cancer Drug Resistance special issue

“…Targeted drugs, in particular antiangiogenic drugs, are today approved for the treatment of hepatocellular carcinoma, in which, however, they are endowed with low efficacy. Alonso-Peña et al [ 27 ] reviewed molecular alterations (mainly, germline polymorphisms and somatic mutations) that have been suggested to confer drug resistance to liver cancers (i.e., hepatocellular carcinoma and cholangiocarcinoma). However, despite the availability of a relevant number of studies that report potential associations among polymorphisms/mutations in genes codifying transporters or detoxifying enzymes, changes in molecular targets, enhanced DNA repair mechanisms, altered balance between survival and apoptosis pathways, tumor microenvironment and epithelial-mesenchymal transition, and cytotoxic or targeted anticancer drug efficacy and/or toxicity, no solid data are currently available and further investigation is needed.…”

Microvesicles: the functional mediators in sorafenib resistance

“…After hepatocellular uptake, sorafenib was N-oxidized by CYP3A4, one of the drug-metabolizing enzymes, to the pharmacologically active sorafenib-N-oxide metabolites [ 51 , 52 ] . However, CYP3A4 was identified as poorly expressed in liver cancer [ 53 ] . Well-studied oncomiRs (e.g., miR 21, miR-142 and miR-27b) overexpressed in HCC, which could be transferred by tumor-derived microvesicles (TMVs), were proved to be negatively associated with CYP3A4 mRNA in human liver [ 54 ] , which might downregulate the expression of this main enzyme and thus could inhibit the active biotransformation of sorafenib drug.…”

Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

“…Moreover, this study has reported other OCT1 mutations including c.262delT (p.Cys88Alafs*16) (*: position of new termination site represented by position number following) and c.181delCGinsT (p.Arg61Serfs*10). Such SNPs and mutations were manifested in lower sorafenib uptake thus, poorer clinical outcomes [38].…”