Gastrointestinal Stromal Tumor Management and Treatment Strategies

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the digestive tract, arising predominantly from activating mutations in KIT or PDGFRA receptor tyrosine kinases. Early diagnosis relies on imaging, endoscopic biopsy and immunohistochemistry, with surgical resection remaining the only curative option for localised disease. The advent of tyrosine kinase inhibitors (TKIs) has revolutionised systemic management, with imatinib as first-line therapy for advanced or metastatic GIST. Despite high initial response rates, resistance almost invariably emerges through secondary mutations or alternative signalling mechanisms, prompting sequential use of sunitinib, regorafenib and more recently ripretinib or avapritinib for specific mutational subtypes. Emerging approaches include molecular profiling via circulating tumour DNA to personalise TKI selection, structural design of next-generation inhibitors to overcome resistance, modulation of endoplasmic reticulum stress pathways and exploration of immunotherapeutic strategies. Continued integration of genomic insights, biomarker-driven treatment and novel agents aims to prolong progression-free and overall survival, while maintaining quality of life.

Research from Nature Portfolio

Recent studies have demonstrated that analysis of circulating tumour DNA can stratify patients by KIT mutational subgroups to predict differential benefit from ripretinib versus sunitinib, revealing that exon-11 plus exon-17/18 mutations fare better with ripretinib, whereas exon-11 plus exon-13/14 mutations derive greater benefit from sunitinib. In parallel, high-resolution crystal structures of avapritinib bound to wild-type and mutant forms of PDGFRA and KIT have identified a novel Gα-pocket within the kinase domain. Medicinal chemistry efforts guided by these structures have yielded avapritinib derivatives designed to overcome resistance mutations and potentially reduce central nervous system penetration, laying the groundwork for next-generation targeted agents.

Gastrointestinal Stromal Tumor Management and Treatment Strategies publication trend

The graph below shows the total number of articles in gastrointestinal stromal tumor management and treatment strategies across all publications each year (not limited to Nature Index journals).

Technical terms

Tyrosine kinase inhibitor (TKI): A small-molecule drug that blocks the activity of kinases such as KIT or PDGFRA, preventing downstream signalling that drives tumour growth.

Circulating tumour DNA (ctDNA): Fragments of DNA shed into the bloodstream by tumour cells, used as a non-invasive biomarker for mutation profiling and treatment monitoring.

Progression-free survival (PFS): The length of time during and after treatment in which a patient’s disease does not worsen.

Unfolded protein response (UPR): A cellular stress pathway activated by accumulation of misfolded proteins in the endoplasmic reticulum, which can promote tumour cell adaptation and survival.

Golgi apparatus: A cellular organelle involved in protein processing and trafficking; aberrant localisation of mutant KIT here can sustain oncogenic signalling.

References

1. Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial. Nature Medicine (2024).
2. Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers. Molecular Cancer (2023).
3. Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA. Nature Communications (2024).
4. Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT. Cell Death & Differentiation (2023).
5. The standard diagnosis, treatment, and follow-up of gastrointestinal stromal tumors based on guidelines. Gastric Cancer (2015).
6. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. British Journal of Cancer (2019).