A team of researchers from the First Affiliated Hospital of Zhengzhou University announced on June 23 that they have uncovered a previously unknown molecular mechanism that amplifies KIT activity in gastrointestinal stromal tumors (GISTs). The findings, published on May 27, 2026, in Precision Clinical Medicine, reveal that the glycosyltransferase GALNT7 directly interacts with KIT and catalyzes O-GalNAc glycosylation, which increases KIT protein stability.
GISTs are the most common mesenchymal tumors of the digestive tract. Approximately 75% to 80% of cases are driven by mutations in the KIT gene. Tyrosine kinase inhibitors have improved treatment for advanced GIST; however, resistance to these drugs remains a significant clinical challenge. The molecular mechanisms sustaining KIT activity beyond its initial mutations have not been fully understood.
The research team integrated bulk RNA sequencing, proteomic data, and single-cell RNA sequencing from GIST patients. They found that O-glycosylation signatures were enriched in high-risk tumors and identified GALNT7 as a key gene upregulated in aggressive GISTs. Laboratory experiments showed that reducing GALNT7 suppressed tumor cell proliferation and invasion, while overexpression had the opposite effect. Mechanistically, GALNT7 was shown to bind to KIT and add GalNAc sugar units to it. This modification prolongs KIT’s half-life by preventing its degradation and sustains activation of PI3K/AKT and MAPK/ERK1/2 signaling pathways—both important drivers of malignancy.
In mouse models, knocking down GALNT7 reduced tumor growth and liver metastasis while extending overall survival. "We were surprised to find that a sugar-modifying enzyme could have such a profound impact on KIT stability and downstream signaling," the authors said. "What's particularly exciting is that this mechanism reveals an additional layer of KIT regulation beyond genetic mutations—meaning it could represent a new vulnerability in GIST, especially for patients who have already developed resistance to existing tyrosine kinase inhibitors. Targeting this glycosylation pathway may offer a way to disable KIT signaling from a completely different angle."
The study also tested benzyl-α-GalNAc—a small-molecule inhibitor targeting O-glycosylation—as a therapeutic strategy. In both cell lines and animal models, this compound reduced O-GalNAc modification on KIT protein, destabilized it, and reversed aggressive tumor behaviors caused by excess GALNT7 expression, resulting in smaller tumors and fewer liver metastases among treated mice compared with controls.
According to the researchers' findings, GALNT7 could serve as both a prognostic biomarker and therapeutic target for GISTs resistant to current treatments.
