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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 681

are more than 840,000 new cases of PLCs diagnosed each year and, due to their late diagnosis and poor
prognosis, this is accompanied by high mortality, which accounts for approximately 8% of deaths due to
cancer.

The most frequent PLC is hepatocellular carcinoma (HCC). This is usually diagnosed by imaging techniques
and determination of serum tumor markers, mainly alpha-fetoprotein, followed by confirmatory histological
study of the biopsy . HCC etiopathogenetic is often difficult to define, with different potentially involved
[1]
factors, such as genetic alterations (chromosomal and gene mutations), epigenetic changes, and risk factors
like cirrhosis, metabolic diseases such as NASH, dietary aflatoxin B1 in Asian countries or viral hepatitis .
[2-4]
The best curative option for early stages is surgical resection, liver transplant or radiofrequency ablation.
Unfortunately, HCC is often diagnosed at intermediate or advanced stages. For these patients, the first-line
treatment is transarterial chemoembolization (TACE) in the intermediate stage and systemic chemotherapy
in the case of advanced HCC . The response to conventional chemotherapeutic agents, for instance cisplatin,
[1,5]
interferon, 5-fluorouracil and doxorubicin in the so-called PIAF regimen, is often very poor due to intrinsic
or acquired chemoresistance. Among new targeted drugs, sorafenib, an inhibitor of several tyrosine kinase
receptors (TKR), is currently used as the first-line treatment in patients with advanced HCC . Nevertheless,
[6]
the benefit in terms of median overall survival (OS) is only of 2.8 months [2,5,6] . Regorafenib, another tyrosine
kinase inhibitor (TKI) also approved by FDA, has a similar effect to sorafenib and is now being used as a
second-line treatment for patients who cannot tolerate sorafenib treatment or undergo tumor progression
during sorafenib therapy . Recently, other TKIs have been approved for being used against advanced HCC
[7]
resistant to sorafenib, such as nivolumab, cabozantinib and lenvatinib .
[8]
Cholangiocarcinoma (CCA), the second most frequent type of PLC (10%-15% of all PLCs) is a heterogeneous
group of malignancies derived from the biliary epithelium. Depending on the anatomical location, CCA
is classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) types. CCA etiopathogenesis
has been associated with certain risk factors, such as advanced age, obesity, alcohol consumption, chronic
biliary diseases (e.g., primary sclerosing cholangitis and liver cirrhosis), chronic infection by liver flukes
(e.g., Clonorchis sinensis and Opisthorchis viverrini), viral hepatitis, congenital diseases (e.g., Caroli disease),
drugs or chemicals (e.g., smoking, thorotrast and dioxin). The diagnosis of CCA is usually based on the
combination of imaging techniques, because specific histological and serum biochemical markers are
still under investigation [9,10] . Surgical resection is the best curative therapy for CCA but this option is only
possible in a few cases. For the rest of CCA patients with unresectable or metastatic cancer, conventional
systemic chemotherapy (gemcitabine combined with cisplatin as first-line treatment or gemcitabine alone)
or locoregional therapy, such as TACE, transarterial radioembolization or radiofrequency ablation, could
be an alternative. The use of targeted therapies based on either TKIs, such as erlotinib and lapatinib, or
antibodies, such as bevacizumab, cetuximab, and panitimumab has resulted of little benefit .
[11]
Despite the efforts in the development of novel treatments to improve PLCs outcome, advances have been
modest. One of the most important challenges in PLC pharmacology is to overcome the poor response of
these tumors to anticancer drugs, which is due in part to powerful mechanisms of chemoresistance (MOC).
These include not only impaired gene expression, but also the existence of genetic variants affecting the
function of proteins involved in MOC. Lower intracellular levels of active agents can be mediated by changes
in the transportome resulting in impaired drug uptake (MOC-1a), enhanced drug export (MOC-1b), or
alterations in drug metabolism that could lead to impaired prodrug activation or increased proportion of
inactive metabolites (MOC-2). Additionally, alterations in: i) target genes of antitumor drugs, ii) the activity
of mechanisms involved in DNA repair and iii) unbalance between survival and apoptosis factors, are
involved in chemoresistance. These processes are classified into MOC-3, MOC-4 and MOC-5, respectively.
Finally, the role of changes related to tumor environment (MOC-6) and epithelial-mesenchymal transition
(EMT, MOC-7) in PLC chemoresistance is still poorly understood [Figure 1] .
[12]