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Page 8 of 20 Gim et al. Hepatoma Res 2023;9:51 https://dx.doi.org/10.20517/2394-5079.2023.90

trametinib combination regimen demonstrated manageable side effects. In light of these results, the FDA
approved dabrafenib plus trametinib as a subsequent line of therapy for BTC with BRAFV600E
[53]
mutations .

Ongoing phase 1 trials are exploring the response to selective BRAF inhibitors, such as ABM-1310
(NCT05501912, NCT04190628) and BGB-3245 (NCT04249843), in patients with BRAFV600-mutated solid
tumors, including BTCs. Additionally, more studies are needed to evaluate the effectiveness of targeted
therapies in patients with concurrent TP53 and BRAFV600E mutations, as initial findings suggest a more
[54]
aggressive disease and reduced clinical benefits .
Similar to other targeted therapies, the challenge of overcoming resistance to BRAF inhibitors persists. As
evidenced by PFS data, a significant proportion of patients initially responsive to BRAF inhibitors eventually
face resistance, necessitating adjustments in treatment strategies. While several potential mechanisms have
been proposed, the majority of investigations have revolved around melanoma and a limited range of lung
cancer cohorts. Nevertheless, a comprehensive analysis of these findings offers relevant insights that can be
extrapolated to BTC patient populations. Notably, one of the potential mechanisms involves the reactivation
of the MAPK pathway [55-57] , often occurring due to alterations affecting the drug target itself, such as BRAF
copy number gains and MEK2 mutations [58-60] .

As discussed earlier, combination treatment involving BRAF inhibitors and MEK inhibitors has shown
promising results. However, despite this encouraging observation, the development of acquired resistance
to combination therapy remains an inevitable challenge. A study conducted within a melanoma cohort has
highlighted that the mammalian target of rapamycin (mTOR) activation could potentially contribute to the
acquired resistance seen with combined BRAF and MEK inhibition . The mTOR kinase plays an
[61]
important role in cellular proliferation, and aberrant mTOR activation has been noted across various cancer
types [62,63] . Given that both the MAPK/ERK and PI3K/AKT signaling pathways converge into the mTOR
complex 1, this pathway could hold significance for the effectiveness of targeted therapy in patients with
BRAF-mutant melanoma . This potentially implies that the inclusion of an mTOR inhibitor might
[61]
effectively restore sensitivity to BRAF or MEK inhibitors, prompting further exploration for potential
therapeutic interventions.

Human epidermal growth factor receptor 2 inhibitors
HER2, encoded by the ERBB2 gene, is a receptor tyrosine kinase involved in crucial oncogenesis signaling
pathways. Its dysregulation is well-documented in cancer development . Besides its well-known
[64]
significance in breast cancer, emerging evidence suggests its involvement in BTC . HER2 expression shows
[65]
ethnic variations, with a higher prevalence in Asian patients (28.4%) compared to Western patients
[66]
(19.7%) . Additionally, HER2 positivity rates in BTC vary based on tumor location, with reported
alteration rates of 2.2% in iCCA, 7.5% in eCCA, and 12.6% in GBC . Detection of HER2 amplification in
[13]
BTC can be achieved through various testing modalities, including immunohistochemistry (IHC),
fluorescence in situ hybridization (FISH), and NGS techniques, with NGS providing the advantage of
simultaneously evaluating multiple molecular alterations, including HER2 activating mutations, particularly
when diagnostic tissue is limited. However, IHC and FISH remain the more commonly employed
methods .
[67]

Pertuzumab and trastuzumab, two monoclonal antibodies targeting HER2, have shown promise in treating
HER2-positive malignancies . In a phase II MyPathway study (NCT02091141) involving previously treated
[68]
HER2-amplified and overexpressed metastatic BTC patients, the pertuzumab and trastuzumab combination