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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 691

UGT1As and UGT2B7 has been observed in HBV-positive HCC . In addition, down-regulation of UGT1A9
[109]
has been related to lower sorafenib metabolism in microsomes of HCC cells . UGT2B7 is a p53 target gene
[110]
in liver cells that could promote intratumor or systemic metabolism and clearance of cytotoxic agents and
other drugs administered together. Thus, UGT2B7 may be related to reduced efficacy of cancer therapy .
[111]
A novel class of human UGT isoforms, namely i2s, has been described. In comparison to isoforms 1 (i1s),
i2s isoforms utilize the shorter exon 5b instead of incorporating the usual C-terminus exon 5a, which causes
a premature arrest of translation and subsequent loss of the transmembrane domain. Therefore, UGT i2s
isoforms are located at the lumen and cytoplasm rather than at the membrane of the endoplasmic reticulum,
which results in the lack of glucuronidation activity but acting in a dominant-negative manner. Increased
i2 isoforms expression in PLCs has been found . Somatic mutations affecting UGTs described in TCGA
[112]
database are listed in Table 4.

MOLECULAR TARGETS AND SURVIVAL PATHWAYS
Three major types of molecular alterations have been reported to be at the origin of hepatocarcinogenesis: i)
Aberrant cell proliferation and survival due to a constitutive activation of signaling pathways, such as EGFR-
Ras-MAPK, PI3K-AKT-mTOR, HGF/MET, Wnt-β-catenin and others; ii) Deregulation of proapoptotic
machinery elements, such as p53 and Bcl2; and iii) Stimulation of neo-angiogenesis, which is crucial for
tumor development . Mutations in genes involved in these pathways are expected to determine the response
[2]
to drugs acting on these targets.

Molecular targets of chemotherapeutic agents (MOC-3)
Mutations or changes in the expression levels of target genes could prevent efficient drug-target interaction
leading to treatment failure . Although TKIs are useful in the treatment of many tumors, their efficacy is
[113]
often hampered by changes in their targets. For instance, the multikinase inhibitor sorafenib reduces tumor
cell proliferation and angiogenesis in HCC, which is due in part to its interaction with receptors for several
growth factors, such as EGF (EGFR), VEGF (VEGFR) and PDGF (PDGFR) .
[6]

Germline pharmacogenetics
Although somatic mutations are the most frequent changes among the targets of antitumor drugs, some
target genes belonging to the VEGF family are also affected by germline mutations. This is the case of KDR
gene (also known as VEGFR or VEGFR2), in which the germline SNP c.1416A>T (p.Gln472His), has been
described in an East Asian HCC cohort. In this case, patients with two wild-type alleles and heterozygous
(AT) genotype have decreased progression-free survival (PFS) and OS compared with homozygous patients
for the mutant allele (TT) . This polymorphism has also been associated with toxicity and adverse reactions
[114]
to sorafenib, including increasing risk of hypertension and hand-foot skin reactions in TT patients .
[115]
Moreover, this mutation has been linked to the response to capecitabine/oxaliplatin and cyclophosphamide
in colorectal and prostatic tumors, respectively. In addition, the germline polymorphism c.-94C>G
[116]
[117]
at the 5’UTR region of the VEGFA gene has been associated with the outcome of prostatic and colorectal
cancer patients . In HCC, homozygous genotype for the G allele has been related to lower PFS and OS than
[116]
homozygous patients for C allele and heterozygous genotypes .
[118]
Somatic pharmacogenetics
Acquired resistance to TKI treatment can be due to somatic mutations in a wide variety of target genes.
Exome sequencing analysis of 243 HCCs revealed 161 mutated genes which could be classified into 11
recurrent pathways. The most frequently altered pathways were PI3K-AKT-mTOR (51%) and MAPK (43%).
Although target genes of TKIs (EGFR, VEGFR1, KDR, VEGFC, VEGFA and BRAF) were affected by less than
1% of all mutations, these alterations were predicted to have functional consequences . Table 5 summarizes
[119]
mutations described in HCC and CCA. Some of these mutations, for instance affecting EGFR, VEGFR1
and VEGFC, are predicted to alter the function of these proteins . An EGFR polymorphism, c.2369C>T
[119]