Molecularly guided therapy in gastrointestinal malignancies: From established targets to resistance and emerging precision strategies

Table 3 Molecularly targeted therapies in cholangiocarcinoma: Clinical role, evidence, resistance, and emerging strategies

Molecular target/alteration	Approximate frequency	Representative therapy	Current clinical role	Evidence grade	Major resistance mechanisms/emerging strategies	Representative sources
FGFR2 fusion/rearrangement	10%-16%, predominantly intrahepatic CCA	Pemigatinib; futibatinib	Established targeted therapy for previously treated, unresectable, or metastatic FGFR2 fusion/rearranged CCA	A	Acquired FGFR2 kinase-domain mutations, bypass signaling, polyclonal resistance, and intratumoral heterogeneity. Next-generation FGFR inhibitors, ctDNA-guided monitoring, combination approaches, and earlier-line treatment are under investigation	Li et al[65]; Mie et al[57]; Goyal et al[42]; Ellis et al[41]; Xin and Miao[47]
IDH1 mutation	10%–20%, predominantly intrahepatic CCA	Ivosidenib	Established targeted therapy for previously treated IDH1-mutated CCA	A	Clonal evolution, metabolic adaptation, secondary pathway alterations, epigenetic remodeling, and bypass signaling. Combinations with immunotherapy, epigenetic agents, or PARP-directed therapy, as well as earlier-line treatment and ctDNA-guided monitoring, remain investigational	Abou-Alfa et al[66]; Bray and Sahai[51]; Salati et al[50]; Li et al[65]
HER2 amplification/overexpression	5%-15%; more frequent in extrahepatic CCA and gallbladder cancer	Trastuzumab-based combinations; pertuzumab; tucatinib-based combinations; trastuzumab deruxtecan	Molecularly selected treatment option for HER2-positive biliary tract cancers; clinical evidence is emerging and varies according to the agent and study population	B	HER2 heterogeneity, HER2 loss, bypass signaling, and downstream pathway reactivation. Next-generation ADCs, bispecific antibodies, and combination HER2-directed therapies are under investigation	Inoue et al[62]; Theocharopoulos et al[58]
BRAF V600E mutation	3%-5%	Dabrafenib + trametinib	Established molecularly selected targeted therapy for BRAF V600E-mutated biliary tract cancer	A	MAPK pathway reactivation, adaptive signaling, and bypass pathway activation. Additional combination strategies are under investigation	Mie et al[57]; Ellis et al[41]

Evidence grading: Grade A, randomized phase III evidence and/or established standard-of-care treatment; Grade B, prospective phase II evidence or substantial clinical evidence; Grade C, early-phase, retrospective, or otherwise limited clinical evidence; Grade D, preclinical or experimental evidence. Evidence grades reflect the maturity and clinical validation of the available evidence and do not directly indicate the magnitude of treatment benefit. ADC: Antibody–drug conjugate; CCA: Cholangiocarcinoma; ctDNA: Circulating tumor DNA; DDR: DNA damage response; dMMR: Mismatch repair deficient; FGFR2: Fibroblast growth factor receptor 2; IDH1: Isocitrate dehydrogenase 1; MSI-H: Microsatellite instability-high; NTRK: Neurotrophic tyrosine receptor kinase; PARP: Poly (ADP-ribose) polymerase; RET: Rearranged during transfection; TMB-H: Tumor mutational burden-high; TRK: Tropomyosin receptor kinase.