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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 699

samples assayed . These are somatic mutations usually located in exon 3 encoding the N-terminal
[182]
phosphorylation sites of β-catenin. HCC sequencing studies collected in cBioportal database reveal that
most frequent mutations occur in Ser/Thr phosphorylation residues (codons 33, 37, 41 and 45) and in codon
32. The clinical implication of these mutations is controversial. Some studies have associated the presence
of CNNTB1 mutations in HCC with better OS [157,158] , whereas others have linked these mutations to tumor
progression and poor prognosis [159,160] .

The insulin-like growth factor (IGF) signaling cascade is also involved in cell growth and survival, and its
activation plays an important role in the resistance of HCC to TKIs [183,184] . An in vivo assay has demonstrated
the presence of elevated IG2F levels as one of the major mechanisms of acquired resistance to sorafenib in
HCC . In addition, it has been shown that c.747G>T (p.Arg249Ser) mutation in p53, which is very common
[184]
in aflatoxin-induced HCC, is accompanied by enhanced expression of IGF2 and type 1 IGF receptor . This
[185]
suggests a possible link between this p53 mutation and the resistance of HCC to TKIs.
The presence of alterations in Ras/Raf/MEK/MAPK/ERK pathway may play an important role in the response
of CCA to chemotherapy. Mutations in KRAS gene have been observed in different subtypes of CCA, mainly
affecting codon 12, such as c.35G>T (p.Gly12Val), c.35G>A (p.Gly12Asp), c.34G>T (p.Gly12Cys) and c.34G>A
(p.Gly12Ser), with variable incidence depending on the population under study [162,186,187] . These mutations
have oncogenic potential, leading to constitutive stimulation of K-Ras and, consequently, activation of
downstream signaling effectors . Several studies have reported a reduced survival of CCA patients with
[188]
mutations in K-Ras codon 12 [162,189] . These mutations conferred resistance to everolimus in CCA cells .
[163]
Both somatic mutations and reduced copy number of mitochondrial DNA (mtDNA) have been found in a
large proportion of HCC tumors [164,190] . Some of these mutations affect coding regions and result in amino
acid substitution or premature stop codon in polypeptides of respiratory complexes, which presumably leads
to mitochondrial dysfunction. In tumor cells, this impairment results in altered reactive oxygen species
(ROS) production, which can promote activation of survival pathways or changes in the expression of anti-
apoptotic factors, eventually leading to an adverse impact on the response to chemotherapy. This is consistent
with the finding that mtDNA depletion in HCC cells promotes resistance to 5-FU .
[164]

NOVEL MECHANISMS AFFECTING CHEMOTHERAPY EFFICACY
Autophagy and changes in tumor microenvironment
Recent evidences have shown that tumor microenvironmental stress-induced autophagy may contribute
in part to the development of chemoresistance . Thus, in HCC cells treated with oxaliplatin autophagy
[191]
is activated, which favors cell survival . Moreover, oxygen deficiency triggers the activation of hypoxia-
[192]
specific transcription factors, which regulates the expression of genes that increase cancer cell survival and
drug resistance . In addition, these factors are master regulators of the expression of genes involved in the
[193]
phenotypic epithelial-mesenchymal transition (EMT), cell migration (MMP2), homing (CXCR4) and the
establishment of the pre-metastatic niche (LOX) . Somatic mutations in these genes have been described
[193]
in HCC, although their relevance in protein function remains unknown [Table 9].

In the case of CCA, interleukins, like IL-6, released by immune cells present in the tumor microenvironment,
particularly macrophages, can confer resistance to toxic compounds and promote tumor growth. Targeting
tumor microenvironment rather than CCA cells directly may lead to novel therapeutic strategies to treat
this cancer . In the case of HCC, higher expression of IL-6 also seems to be a key player. Moreover, IL-6
[194]
knockdown in HCC cells increased their sensitivity to sorafenib . Whether several somatic mutations
[195]
described in IL-6 gene [Table 9] have any influence in MOC-6 of PLC is poorly understood.