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

Figure 1 Molecular targets and therapeutic strategies in gastrointestinal malignancies. A: Key molecular targets and their associated oncogenic or biological pathways, including EGFR/RAS, HER2, FGFR2, BRAF, KIT/PDGFRA, KRAS, IDH1, CLDN18.2, and BRCA1/2; B: Representative targeted therapies corresponding to the identified molecular targets; C: Tumor-specific applications of molecularly targeted therapies across colorectal cancer, cholangiocarcinoma/biliary tract cancer, gastric/gastroesophageal junction cancer, gastrointestinal stromal tumors (GIST), and pancreatic ductal adenocarcinoma; D: Proposed clinical pathway for molecularly guided treatment, encompassing biomarker testing, selection of targeted therapy, response monitoring, evaluation at disease progression or intolerance, and subsequent treatment adaptation based on molecular reassessment. EGFR: Epidermal growth factor receptor; HRR: Homologous recombination repair; IHC: Immunohistochemistry; PCR: Polymerase chain reaction; NGS: Next-generation sequencing; ctDNA: Circulating tumor DNA; FGFR: Fibroblast growth factor receptor; BRAF: B-Raf proto-oncogene; PDGFRA: Platelet-derived growth factor receptor alpha; PI3K: Phosphatidylinositol 3-kinase; IDH1: Isocitrate dehydrogenase 1; ADC: Antibody-drug conjugate; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; MAPK: Mitogen-activated protein kinase; HER2: Human epidermal growth factor receptor 2; VEGFR: Vascular endothelial growth factor receptor; NTRK: Neurotrophic tyrosine receptor kinase; RET: Rearranged during transfection; KIT: KIT proto-oncogene receptor tyrosine kinase; TKI: Tyrosine kinase inhibitor; CLDN18.2: Claudin 18.2.