Journal: Journal of gastroenterology and hepatology
The article is a narrative review of resistance mechanisms and evolving treatment strategies in gastrointestinal stromal tumors (GIST).
It summarizes:
- Primary biology: Most GISTs are driven by activating mutations in KIT or PDGFRA, with imatinib as foundational therapy for advanced disease.
- Resistance mechanisms
- Genomic: Secondary mutations in KIT/PDGFRA that interfere with TKI binding or stabilize the active kinase conformation, leading to reduced sensitivity or frank resistance.
- Non-genomic/adaptive:
- Dysregulation of noncoding RNAs
- Metabolic reprogramming
- Epigenetic alterations
- Development of an immunosuppressive tumor microenvironment
These collectively create a phenotype less dependent on the original oncogenic driver and more tolerant of TKIs.
- Therapeutic evolution toward precision medicine
- First-line and subsequent therapy increasingly guided by molecular subtype rather than a one-size-fits-all approach.
- Use of circulating tumor DNA (ctDNA) to track emerging resistance mutations and to sequence later-line treatments in real time.
- Expanded role of newer TKIs (e.g., avapritinib, ripretinib, bezuclastinib), each optimized against specific resistance mutation profiles.
- Emerging and experimental strategies
- Boron neutron capture therapy (BNCT) as a kinase-independent approach to overcome resistance.
- Combination strategies integrating:
- Immunotherapies
- Epigenetic modulators
- Pathway-specific inhibitors
These approaches aim to target both the driver oncogene and adaptive resistance programs.
- Clinical implication: The field is moving from static, line-based therapy to a dynamic, personalized treatment model, incorporating liquid biopsy, comprehensive molecular profiling, and rational combinations to delay or overcome resistance and improve long-term outcomes in GIST.