Precision oncology in GI-cancers: Mechanisms of action, indications and ongoing strategies to overcome primary and secondary resistance.

Gastrointestinal (GI) cancers remain a leading cause of cancer mortality, with durable benefit from current therapies limited to a subset of patients. Precision oncology is expanding options by targeting recurrent, actionable alterations, most notably in cholangiocarcinoma (CCA), in genes such as FGFR2, IDH1, KRAS, BRAF and ERBB2. Here, we review the evolving therapeutic landscape, emphasizing clinical efficacy, and indications for various treatment modalities. Key therapies include FGFR inhibitors (first and next-generation; both covalent and FGFR2-selective agents), IDH1 inhibitors, KRAS and BRAF inhibitors combined with EGFR blockade and/or chemotherapy, and HER2-targeted monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs). Central mechanisms of both primary and secondary resistance are detailed, with a focus on on-target mutations and convergent off-target MAPK signaling pathways. Finally, we discuss drug-tolerant persister cells, residual tumor cell states that survive therapy without canonical genetic resistance alterations and may contribute to relapse and secondary resistance.