Targeting KIT and PDGFRA mutations in advanced gist: current and future clinical implications

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) are a paradigmatic example of precision oncology. Identification of KIT and PDGFRA mutations has enabled effective targeted therapies for advanced disease. Although these treatments have significantly improved patient survival, drug resistance remains a major clinical challenge. AREAS COVERED: This narrative review examines advanced KIT/PDGFRA-mutant GIST, including established therapies, mechanisms of resistance, plasma molecular profiling, and emerging therapeutic approaches. Relevant English-language literature available in full text was identified through PubMed searches using terms related to GIST and primary and secondary mutations. Clinical findings are distinguished from exploratory biomarkers and preclinical evidence. EXPERT OPINION: GISTs remain a paradigmatic example of precision oncology, demonstrating how the identification of oncogenic driver mutations can profoundly alter the natural history of a previously chemoresistant malignancy. Over the next five to ten years, we expect treatment pathways to become increasingly guided by genotype, supported by prospective evidence. While more effective kinase inhibition remains important, research should also explore therapeutic targets beyond kinase signaling, including tumor dependencies and interactions with the immune and stromal microenvironment. The clinical value of these approaches will ultimately depend on their ability to translate biological insights into longer survival while preserving quality of life and minimizing treatment burden.