Targeted Therapy for Advanced Gastrointestinal Stromal Tumors: Evolution and Future Directions

Area of Science:

• Oncology
• Gastroenterology
• Molecular Biology

Background:

• Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal mesenchymal tumor, often driven by KIT or PDGFRA mutations.
• While surgery is curative for localized GIST, ~50% of patients experience recurrence or metastasis.
• Tyrosine kinase inhibitors (TKIs) transformed metastatic GIST management, but drug resistance and limited response durability are significant issues.

Purpose of the Study:

• To review current drug treatment strategies for advanced GIST.
• To explore mechanisms of TKI resistance in GIST.
• To discuss future directions in GIST drug development and clinical management.

Main Methods:

• Review of current literature on GIST pathogenesis, treatment, and resistance mechanisms.
• Analysis of challenges posed by intratumoral heterogeneity and acquired resistance.
• Exploration of novel therapeutic strategies and monitoring techniques.

Main Results:

• Activating mutations in KIT or PDGFRA are key to GIST pathogenesis.
• Intratumoral heterogeneity and acquired resistance limit TKI efficacy.
• Current TKIs face challenges including resistance, limited durability, and adverse effects.

Conclusions:

• Advanced GIST management requires addressing drug resistance and intratumoral heterogeneity.
• Future GIST treatment may involve mutation-stratified sequencing and combination TKI therapies.
• Circulating tumor DNA (ctDNA) monitoring offers potential for real-time treatment guidance and resistance surveillance.