Page 76 - Read Online

Page 6 of 10 Ruff et al. Hepatoma Res 2023;9:37 https://dx.doi.org/10.20517/2394-5079.2023.51

Other potential targeted therapies
Dasatinib is a multi-tyrosine kinase inhibitor. One theory is that the changes to cell differentiation,
metabolism, and epigenetic control caused by IDH mutations may confer targetable vulnerabilities in other
pathways. One pre-clinical study performed a high-throughput drug screen with 17 BTC cell lines. They
demonstrated rapid apoptosis in dasatinib-treated, IDH-mutated ICCA cell lines due to a dependency on
SRC signaling. SRC is a family of non-receptor tyrosine kinases that are known to play a role in cell
proliferation, differentiation, and migration . In the IDH-mutated patient-derived xenografts, dasatinib
[44]
caused widespread cell necrosis. Of note, levels of SRC expression and activity did not correlate with IDH
mutation status or dasatinib sensitivity. In addition, SRC activity was similar in both the IDH wild-type and
mutated cell lines. There is currently a phase II trial evaluating the use of dasatinib in patients with IDH-
mutated advanced CCA (NCT02428855).

Other pre-clinical studies have demonstrated that the bromodomain and extra-terminal domain (BET)
[45]
inhibitor JQ1 has an inhibitory effect on IDH-mutated ICCA human cell lines . BET represents a family of
proteins that facilitate transcriptional activation through recruitment of transcriptional regulatory
[46]
complexes . Ongoing clinical trials for IDH-mutated CCA can be found in Table 1.

Mechanisms of resistance
Despite the promising future of targeted therapy, a critical hurdle is IDH inhibitor resistance. Resistance can
be broken down into primary and secondary (or acquired) resistance. When a tumor does not initially
respond to targeted therapy, this is known as primary resistance. On the other hand, secondary resistance
occurs when patients demonstrate disease recurrence or progression after an initial response to targeted
therapy. Understanding the mechanisms of resistance can guide clinicians as to which targeted therapies
will be most effective in patients and how to predict acquired resistance so that treatment regimens can be
adjusted.

IDH inhibitor resistance in acute myeloid leukemia
Most studies focused on IDH inhibitor resistance have been in acute myeloid leukemia. In a study of 174
patients with acute myeloid leukemia, the presence of concurrent receptor tyrosine kinase (RTK) pathway
mutations was associated with primary resistance to ivosidenib and the development of RTK pathway gene
mutations during treatment was associated with secondary resistance. Additionally, restoration of elevated
2-HG levels through acquired second-site IDH1 mutations or new IDH2 mutations was observed as a
mechanism of secondary resistance . Wang et al. performed a genomic analysis in longitudinally collected
[47]
specimens from 60 patients with IDH1 or IDH2 mutated acute myeloid leukemia and treated with IDH
inhibitors. They demonstrated that primary resistance to IDH inhibitors was associated with certain
co-mutations (RAS and RUNX1) and with leukemia stemness. Secondary resistance was associated with the
acquisition of new mutations. Interestingly, one of these was an acquired TET2 mutation . As discussed
[48]
earlier in this review, we noted that Wu et al. demonstrated the importance of TET2 inactivation in IDH-
mutated cholangiocarcinoma immune evasion .
[26]

In a study of four patients, mutant IDH isoform switching, either from mutated IDH1 to mutated IDH2 or
vice versa, was identified as a mechanism of acquired resistance. Isoform switching re-established elevated
2-HG levels. Three of these patients had acute myeloid leukemia, while the fourth had IDH1 mutated ICCA.
In the patient with ICCA, sequencing of the post-progression biopsy after treatment with ivosidenib
demonstrated the known IDH1 mutation and a new IDH2 mutation. The patient was then treated with an
IDH2 inhibitor, enasidenib, that is approved for acute myeloid leukemia, but unfortunately expired about 2
months after starting treatment .
[49]