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

Abstract

Gastrointestinal (GI) malignancies comprise a heterogeneous group of cancers in which molecular alterations increasingly guide therapeutic selection. Biomarker-driven therapies are established in selected colorectal, gastric and gastroesophageal junction, biliary, pancreatic, and GI stromal tumors. However, primary and acquired resistance, tumor heterogeneity, evolving molecular profiles, and unequal access to molecular diagnostics limit durable benefit. This narrative review evaluates the current landscape of molecularly targeted therapies across major GI malignancies, focusing on validated molecular targets, clinical evidence, biomarker selection, resistance mechanisms, and emerging therapeutic strategies. A structured literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar for publications from January 2000 to 30 July 2026. Evidence was narratively synthesized according to tumor type and molecular target and graded as A (randomized phase III evidence or established standard of care), B (prospective phase II or substantial clinical evidence), C (early-phase, retrospective, or limited clinical evidence), or D (preclinical or experimental evidence). Molecularly targeted therapy is now an established component of treatment for selected molecular subgroups. Key advances include genotype-directed therapy in colorectal cancer and cholangiocarcinoma, human epidermal growth factor receptor 2- and claudin 18.2-directed approaches in gastric cancer, KIT proto-oncogene receptor tyrosine kinase/platelet-derived growth factor receptor alpha-directed treatment in GI stromal tumor, and molecularly selected strategies in pancreatic cancer. Resistance, intratumoral heterogeneity, molecular evolution, and inconsistent biomarker assessment remain major barriers. Emerging approaches include next-generation inhibitors, antibody–drug conjugates, bispecific antibodies, cellular therapies, circulating tumor DNA-guided treatment, targeted–immunotherapy combinations, and tissue-agnostic strategies. Further progress will require accessible biomarker testing, longitudinal molecular assessment, rational treatment sequencing, and prospective evaluation of emerging precision therapies.

Keywords: Gastrointestinal neoplasms; Precision medicine; Tumor biomarkers; Neoplasm drug resistance; Antineoplastic agents

Core Tip: Molecularly targeted therapy has transformed the management of selected gastrointestinal malignancies by linking specific genomic or protein alterations to individualized treatment. This narrative review summarizes established and emerging molecular targets across colorectal, gastric and gastroesophageal junction, biliary, pancreatic, and gastrointestinal stromal tumors, while contextualizing therapies according to clinical evidence, biomarker requirements, and resistance mechanisms. Emerging approaches—including circulating tumor DNA, antibody–drug conjugates, bispecific antibodies, KRAS-directed therapies, and targeted–immunotherapy combinations—may help address treatment resistance, although their clinical roles vary in maturity and require continued prospective evaluation.