The Mechanisms of Imatinib Resistance in Gastrointestinal Stromal Tumours: Theoretical Basis and Therapeutic Aspect.

Imatinib is a small molecule that inhibits receptor tyrosine kinases KIT and platelet-derived growth factor receptor α (PDGFRA). It was approved by the U.S. Food and Drug Administration (FDA) in 2002 for the treatment of advanced, unresectable gastrointestinal stromal tumours (GISTs). Since then, additional kinase inhibitors targeting multiple pathways have also been introduced. However, as treatment with imatinib is prolonged, its effectiveness gradually declines, with 50% of patients experiencing relapse within 2-5 years. This decline in effectiveness is largely attributed to the development of both initial and acquired resistance. Due to these mechanisms of resistance, many advanced GIST patients struggle to achieve long-term benefits from systemic treatment. This review aims to summarise the mechanisms of resistance to imatinib and their relationship with GIST molecular subtypes, while also exploring the latest strategies to overcome resistance. We discuss the alterations in signalling pathways following imatinib resistance, the disruption of autophagy and glycolysis, the role of microRNAs and immunotherapy in resistant GISTs, and combination therapies. Furthermore, we examine ongoing clinical trials and potential future therapies that could be integrated into clinical practice, offering guidance for new treatment strategies that aim to enhance the prognosis of advanced GIST patients.