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Page 698 Alonso-Peña et al. Cancer Drug Resist 2019;2:680-709 I http://dx.doi.org/10.20517/cdr.2019.006

Caspase 8 plays a key role in signal transduction within the extrinsic apoptotic pathway. Somatic mutations
with loss-of-function affecting this protein have been associated with the resistance to drugs whose
mechanism of action includes apoptosis activation . In a study of 69 HCC patients, 9 of them had the
[169]
same alteration in the caspase 8 gene (CASP8), c.1225_1226delTG, a frameshift mutation with two base-
pair deletion resulting in a defective protein with a shorter p10 protease subunit . Mutations affecting p10
[154]
subunit of procaspase-8 have been reported to promote unresponsiveness to chemotherapy in other cancers,
such as acute myeloid leukemia . Whether these mutations are also involved in HCC chemoresistance is
[170]
not known.

Alterations in anti-apoptotic/pro-survival factors (MOC-5b)
Aberrant expression and/or activating mutations in anti-apoptotic factors as well as constitutive activation
of pro-survival signaling pathways, such as PI3K/AKT, Ras/Raf/MAPK/ERK/MEK or JAK/STAT, lead
to an uncontrolled cell proliferation and evasion of apoptosis in cancer cells, which contributes to tumor
progression and reduces effectiveness of chemotherapeutic drugs.

The PI3K/PTEN/AKT/mTOR pathway, commonly altered in HCC, is associated with poor prognosis . The
[171]
frequency of PIK3CA mutations in HCC is controversial, ranging from 0 to 36% of HCC cases depending
on the population studied [172,173] . Some of the most recurrent PIK3CA mutations in HCC samples according
to the data from COSMIC, such as c.3204_3205insA (p.Asn1068fs*4) and c.3140A>G (p.His1047Arg) are
oncogenic [174,175] . Other mutations described in HCC, such as c.1624G>A (p.Glu542Lys) and c.1633G>A
(p.Glu545Lys), affecting the PIK helical domain of the protein confer gain-of-function . Although PIK3CA
[175]
mutations have not been directly related to chemoresistance in HCC, an in vitro assay has reported PIK3CA
overexpression in sorafenib-resistant HCC cells .
[176]
The tumor suppressor gene PTEN is the major negative regulator of PI3K/AKT/mTOR pathway. Therefore,
alterations leading to PTEN loss-of-function could induce the activation of this pathway. Even though PTEN
mutations are uncommon in HCC, somatic loss of heterozygosity of PTEN allele has been found in 20%-
30% of HCC cases [165,166] . Moreover, PTEN down-regulation may be also caused by epigenetic alterations .
[177]
These changes are clinically relevant because PTEN expression has been found to be decreased in sorafenib-
resistant HCC cells . Therefore, activation of PI3K/AKT/mTOR pathway due to impaired PIK3CA
[176]
and PTEN genes may play a key role among MOC accounting for the lack of response of HCC patients
to sorafenib. At this respect, several preclinical and clinical studies have been carried out to evaluate the
efficacy of inhibitors targeting PI3K/PTEN/Akt/mTOR pathway. Some of them have shown promising
results . For instance, inactivating mutations in TSC1/2 genes have been found both in HCC cell lines and
[178]
clinical specimens, resulting in an impairment of mTOR signaling. However, HCC cells harboring these
mutations were sensitive to rapamycin, an mTOR inhibitor . TSC2-null HCC cell lines have also shown to
[167]
be sensitive to everolimus, another mTOR inhibitor, and HCC patients with low expression of TSC2 treated
with everolimus have higher OS rates .
[179]
Regarding JAK/STAT signaling pathway in HCC tumors, somatic mutations mainly affecting domains of
JAK1 (pseudo-kinase and tyrosine kinase) have been identified, which lead to constitutively activated JAK/
STAT signaling . Since JAK/STAT pathway is involved in acquired resistance of HCC cells to sorafenib ,
[180]
[161]
these findings suggest that mutations in JAK1 may lead to failure of sorafenib treatment due to compensatory
proliferation. Thus, mutated JAK1 could be a potential target for pharmacological manipulation. Indeed,
cells harboring c.2108G>T (p.Ser703Ile) variant were sensitive to ruxolitinib, a JAK1/2 inhibitor .
[181]
Wnt/β-catenin signaling pathway is frequently deregulated in HCC, leading to β-catenin accumulation
in the nucleus of cancer cells . Aberrant activation of this pathway is largely due to gain-of-function
[159]
mutations in CTNNB1 gene, encoding β-catenin protein, which have been observed in 20%-40% of HCC