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Casolino et al. Hepatoma Res 2021;7:76 https://dx.doi.org/10.20517/2394-5079.2021.79 Page 17 of 23

TWEAK/Fn14 pathway is also increasingly expressed in CCA. It not only supports tumour proliferation but
also modulates migration and polarisation of TME cells, including macrophages and CAFs. The
pharmacological inhibition of TWEAK/Fn14 and of its downstream signals significantly reduced CCA
xenograft growth, inflammation and fibrosis, while TWEAK overexpression drove cancer-associated
fibroblast proliferation and collagen deposition in the tumour niche in preclinical models .
[115]
These preliminary studies indicate that targeting TME is a promising therapeutic strategy to further
investigate in clinical trials.

Other potential therapeutic targets on the horizon
In addition to those discussed in the previous sections, many other potential targets include DNA damage
response (DDR), MET aberrations, PI3K/AKT/mTOR signalling pathway, and chromatin remodelling gene
alterations (ARID1, BAP1 and PBRM1).

DDR can be found in up to 60% of BTCs and may offer several therapeutic advantages with PARP
inhibitors (PARPi) [116,117] . Inactivation of BRCA1 and BRCA2 genes is the most frequent event associated
[119]
[118]
with DDR . In a retrospective multicentric study, Golan et al. demonstrated that 4/18 CCA patients
with BRCA pathogenic variants (somatic or germline) treated with PARPi achieved a favourable response in
first or subsequent lines, of whom one experienced sustained disease response with a PFS of 42.6 months.
The 44% of patients (8/18) had a previous personal or a family history of BRCA-associated cancer (breast,
ovarian, prostate and pancreatic cancer).

Several PARPi are currently being investigated in BTCs patients, including olaparib, rucaparib, and
niraparib, as single agents or associated with other strategies [Table 3]. In particular, the combination of
PARPi and IDH1 inhibitors or ICIs is based on the preclinical rationale of potential synergistic activity.
Mutations in IDH gene are shown to significantly decrease homologous recombination repair activity by
inhibiting the αKG-dependent dioxygenases, therefore enhancing the sensitivity to PARPi . Ongoing
[120]
clinical trials are exploring the efficacy of PARPi in IDH1/2 mutant iCAA in order to assess their synthetic
lethality and to target IDH1/2-related dependencies (NCT03212274, NCT03878095).

Treatment with PARPi has also been associated with increased genomic instability, immune pathway
activation, and PD-L1 expression on cancer cells, which might promote responsiveness to ICIs .
[121]
High c-Met expression and MET amplifications are described in up to 16% and 7% of BTCs, respectively .
[122]
Cabozantinib is a multi-kinase inhibitor of MET, already approved for the treatment of advanced renal cell
and thyroid carcinoma . It showed limited activity and significant toxicity in a study of 19 unselected,
[123]
previously treated, BTCs patients with a mPFS and mOS of 1.8 (95%CI: 1.6-5.4) and 5.2 (95%CI: 2.7-10.5)
months, respectively . However, the administration of this agent-based on molecular selection may be
[124]
more effective.

Mutations in the PI3K/AKT/mTOR signalling pathway have been described in 40% of eCCA and 25% of
iCCA (25%) [125,126] . Preclinical studies have shown activity of PI3K/AKT/mTOR inhibition in BTCs,
suggesting that this therapeutic strategy may have clinical utility for a subset of BTCs harbouring
aberrations in this pathway . However, despite initial enthusiasm from clinical studies with rapamycin
[125]
analogues, showing interesting activity with an acceptable toxicity profile, novel strategies exploring AKT
and PI3K inhibitors have raised serious safety concerns, highlighting the need for improved patient
selection and increased target specificity for the clinical development of these agents . Several ongoing
[126]