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Alonso-Peña et al. Cancer Drug Resist 2019;2:680-709 I http://dx.doi.org/10.20517/cdr.2019.006 Page 683

CHANGES IN INTRACELLULAR CONCENTRATIONS OF ACTIVE ANTICANCER AGENTS
Many anticancer drugs perform their therapeutic action inside tumor cells. For this reason, mechanisms
reducing their intracellular concentrations impair the effectiveness of the treatment. In this sense, changes in
the activity of transporters accounting for drug uptake or efflux could determine the capability of anticancer
drugs to reach their molecular targets. Moreover, some drugs are administered as prodrugs, which means
that they need to be metabolized intracellularly to generate active compounds. In contrast, other drugs
are rapidly biotransformed into inactive metabolites. Thus, changes in the expression and activity of drug-
metabolizing enzymes can determine the overall response to chemotherapy.

Mutations affecting the transportome (MOC-1)
Two main superfamilies of transporters are involved in MOC-1: Solute carrier (SLC) proteins and ATP-
binding cassette (ABC) proteins. Members of the first group are involved in the uptake of a wide range of
molecules, while several ABC pumps use the energy released by the ATP hydrolysis to export their substrates
from the cells.

Genetic variants in genes involved in drug uptake (MOC-1a)
Among drug uptake transporters, those encoded by SLCO, SLC22A and SLC31A gene families have been
extensively described as main players in the transport of anticancer drugs used against HCC and CCA, such
as platinum derivatives and TKIs. Moreover, SLC28A and SLC29A gene families, which encode transporters
able to carry out concentrative (CNT) and equilibrative (ENT) nucleoside uptake, are involved in the response
[14]
to nucleoside and pyrimidine base analogs, such as gemcitabine and 5-FU . Accordingly, mutations affecting
these genes could modify the response of HCC and CCA to their substrates. Until now, most investigations
have been focused on the association between gene expression and drug resistance. There is also information
on the role of germline mutations in antitumor drug pharmacokinetics. In contrast, there is only a few
studies regarding somatic mutations affecting SLC transporters in HCC and CCA. Available information
can be obtained from COSMIC (https://cancer.sanger.ac.uk/cosmic) and TCGA (https://cancergenome.nih.
gov/) databases. Table 1 provides a summary of mutations affecting SLCO, SLC22A, SLC28A, SLC29A and
SLC31A genes in HCC and CCA.

Germline pharmacogenetics: Among the members of SLCO gene family, OATP1B1 (SLCO1B1) and OATP1B3
(SLCO1B3), which have redundant substrate specificity, have been characterized as transporters of TKIs,
including sorafenib . Several in vivo and in vitro studies have described SNPs or haplotypes that result
[15]
in altered expression, localization and activity of OATPs. Most research has been focused on germline
polymorphisms of OATP1B1 and OATP1B3 affecting pharmacokinetics and response of statins and paclitaxel,
respectively . Two germline mutations in OATP1B1, c.388A>G (p.Asn130Asp) and c.521T>C (p.Val174Ala),
[16]
have been associated with side effects after treatment of HCC patients with sorafenib. However, none of
[17]
the investigated polymorphisms has been associated with the survival of these patients . In patients with
unresectable liver metastasis from colorectal cancer, genetic variants of OATP1B3 (c.334T>G; p.Ser112Ala
and c.699G>A; p.Met233Ile) and OCT1 (SLC22A1, c.1260_1262delGAT; p.Met420del) have been linked to
neutropenia and diarrhea, respectively, when they were treated with hepatic artery infusion of irinotecan,
[18]
oxaliplatin and 5-FU, and intravenous cetuximab . Several OCT3 (SLC22A3) variants have been studied,
but none of them have been related neither to HCC nor to CCA [19,20] .

On the other hand, germline mutations in SLC28A and SLC29A genes affecting gemcitabine effectiveness
[21]
have been identified in breast cancer and non-small-cell lung cancer [22,23] . Unfortunately, there are no
similar studies in PLCs.

CTR1 (SLC31A1) is a copper transporter involved in the uptake of platinum derivatives. The study of the
relationship between CTR1 polymorphisms and the response of CCA to the therapy with gemcitabine plus