Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, with its pathogenesis primarily linked to activating mutations in the KIT or platelet derived growth factor receptor alpha (PDGFRA) genes. Surgical resection remains the standard curative treatment for localized GIST; however, ~50% of patients eventually develop recurrence or metastasis. Since the introduction of imatinib in the early 21st century, the management of metastatic GIST has shifted from solely surgical intervention to a systemic, chronic disease management model centered on tyrosine kinase inhibitors (TKIs). However, during the course of treatment, most patients develop drug resistance. Despite the transformative impact of TKIs, some critical clinical challenges remain unresolved. Intratumoral heterogeneity, in particular, poses a significant obstacle, as tumors often comprise diverse populations of cells with varying genetic and molecular profiles. This diversity means that while some subclones may initially respond well to TKI therapy, others harboring inherent or acquired resistance mutations can continue to proliferate, ultimately leading to treatment failure. Additionally, the limited durability of TKIs responses, even in tumors initially sensitive to treatment, remains a pressing concern. Moreover, the lack of curative systemic options for advanced GIST, along with adverse drug reactions, underscores the unmet needs within this patient population. These challenges underscore the necessity of this review, which discusses current standard drug treatment strategies for advanced GIST, including sequential TKIs therapy and investigations into mechanisms of drug resistance. Finally, the review explores precise and actionable future directions for GIST drug development and clinical management, including mutation-stratified therapeutic sequencing, rational TKI-based combination regimens, and circulating tumor DNA (ctDNA)-guided real-time treatment monitoring and resistance surveillance.