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Yang et al. Hepatoma Res 2023;9:48 https://dx.doi.org/10.20517/2394-5079.2023.68 Page 9 of 21

[34]
of this metabolite can competitively inhibit the activity of α-KG-dependent dioxygenases . Additionally,
+
IDH1/2 mutations not only decrease the ability of NADP to be reduced to NADPH, but also promote the
reverse conversion of NADPH to NADP . Excessive accumulation of 2-HG and impaired NADPH
+[35]
production jointly result in epigenetic changes, DNA repair damage, and aberrant cell metabolism, thereby
promoting tumorigenesis .
[36]
The oncogenic transformation of IDH1/2 is due to arginine 132 (R132) in IDH1, and either R140 or R172 in
IDH2. Notably, mutations in IDH1 and IDH2 are mutually exclusive events in iCCA. The oncogenic
metabolite 2-HG, produced as a result of IDH1 R132 mutation, directly binds to DNMT1 and promotes its
association with the promoter region of RIP3. This leads to an increase in DNA methylation levels on the
RIP3 promoter and a decrease in RIP3 expression, ultimately hindering cellular necrosis . IDH1 mutations
[37]
induce metabolic reprogramming and iCCA tumorigenesis through PFKP-induced aerobic glycolysis and
AMPK activation , and inhibit interferon-TET2 signaling to promote immune evasion and tumor
[38]
[39]
maintenance . IDH2 mutations increase the dependence of cells on mitochondrial oxidative
phosphorylation and reduce glycolysis under hypoxia . Xiang et al. characterized the intratumor
[40]
heterogeneity (ITH) landscape of iCCA patients by utilizing exome sequencing and bulk RNA sequencing
techniques . The subgroup of IDH mutation (IDH-SG) is less associated with TME, and presents reduced
[23]
T-cell infiltration and decreased T-cell toxicity. This result was also confirmed in single-cell sequencing. In
all types of BTC, IDH1/2 mutations only occur in iCCA, and IDH1 mutations are more common, with an
incidence of 5%-24%. The prognostic impact of IDH mutations in patients with BTC remains unclear. Some
reports showed that IDH mutations are associated with better prognosis in iCCA patients, with longer
mOS, smaller tumor size, and less tumor recurrence [41-44] . However, others suggested that IDH mutations
have no prognostic impact on iCCA. Goyal et al. analyzed 104 iCCA patients (25.0% IDH1 mutation, 3.8%
IDH2 mutation) and found no significant difference in mOS between IDH-mutant and IDH-wild type
[45]
patients (15.0 vs. 20.1 months, P = 0.17) . In lymph node-negative patients, IDH mutations did not impact
prognosis . In addition, a propensity score matching analysis showed that IDH1/2 mutations did not
[46]
exhibit higher homologous recombination defects and were not associated with increased sensitivity to
[47]
platinum-based chemotherapy .
Ivosidenib
To date, IDH1 inhibition has shown promising application prospects in iCCA patients with IDH1
mutations. Based on the findings of the ClarIDHy trial, ivosidenib was granted FDA approval as a second-
line therapy for cholangiocarcinoma in 2021. ClarIDHy, a phase 3 randomized (2:1) trial, enrolled 185
previously treated cholangiocarcinoma patients carrying IDH1 mutations, and assessed the safety and
efficacy of ivosidenib in such patients (124 receiving ivosidenib vs. 61 receiving placebo) . The ORR of
[48]
ivosidenib arm was 2.4%. However, compared to the placebo arm, the ivosidenib arm had significantly
longer mPFS [2.7 vs. 1.4 months; HR 0.47 (95%CI 0.33- 0.68)]. After adjustment of the crossover of 70%
placebo patients to ivosidenib, mOS was also better with ivosidenib [10.8 vs. 6.0 months; HR:0.46 (95%CI
0.28-0.75)]. The most common TRAEs of ivosidenib were nausea (38%), diarrhea (32%), as well as fatigue
(28%).

Other IDH inhibitors
Apart from ivosidenib, other inhibitors targeting IDH1 (AB-218), IDH2 (Enasidenib), as well as dual IDH1/
2 inhibitors (HMPL-306; LY3410738) are currently under investigation. PARP inhibitors (Olaparib;
AZD6738) and PARP inhibitors combined with immune checkpoint inhibitors (Olaparib plus Durvalumab)
are being evaluated for IDH1-mutant iCCA with impaired homologous recombination repair through an
alternative approach of synthetic lethality [Supplementary Table 1].