Scientists uncover new molecular mechanism driving gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract, with KIT mutations driving approximately 75% to 80% of cases. While tyrosine kinase inhibitors (TKIs) have transformed treatment for advanced GIST, primary and acquired resistance remain major clinical hurdles. The KIT signaling pathway continues to drive malignancy even when TKIs fail, yet the molecular mechanisms that sustain KIT activity beyond its initial mutations have remained poorly understood. Based on these challenges, there is an urgent need to investigate additional regulatory mechanisms that control KIT-driven oncogenic signaling and malignant progression.

A team of researchers from the First Affiliated Hospital of Zhengzhou University has now uncovered a previously unknown mechanism by which KIT activity is amplified in GIST. Their findings, published (DOI: 10.1093/pcmedi/pbag016) on May 27, 2026, in Precision Clinical Medicine, reveal that the glycosyltransferase GALNT7 directly interacts with KIT and catalyzes a specific type of sugar modification—O-GalNAc glycosylation—that dramatically increases KIT protein stability.

The researchers integrated bulk RNA-seq, proteomic, and single-cell RNA-seq data from GIST patients and found that O-glycosylation signatures were strongly enriched in high-risk tumors. Among all glycosylation-related genes, GALNT7 emerged as a hub—its expression was significantly upregulated in aggressive GISTs and correlated with poor progression-free survival. In laboratory experiments, knocking down GALNT7 suppressed GIST cell proliferation, migration, and invasion, while overexpressing it had the opposite effect. Mechanistically, the team demonstrated that GALNT7 physically binds to KIT and adds GalNAc sugar units to the receptor. This O-GalNAc modification prolongs KIT's half-life, preventing its normal degradation and sustaining activation of the PI3K/AKT and MAPK/ERK1/2 signaling pathways—two critical drivers of GIST malignancy. In mouse models, GALNT7 knockdown dramatically reduced both subcutaneous tumor growth and liver metastasis, while significantly 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 evaluated benzyl-α-GalNAc, a small-molecule O-glycosylation inhibitor, as a therapeutic strategy. In GIST cell lines and animal models, this compound effectively reduced KIT O-GalNAcylation, destabilized the KIT protein, and reversed the aggressive phenotypes driven by GALNT7 overexpression. Treated mice showed significantly smaller tumors and fewer liver metastases compared with controls. These findings position GALNT7 as both a promising prognostic biomarker and a therapeutic target. More broadly, the work opens a new frontier in understanding how post-translational modifications—specifically glycosylation—can amplify oncogenic signaling in cancers driven by receptor tyrosine kinases. For GIST patients facing drug resistance, targeting the GALNT7-KIT glycosylation axis may offer a potential alternative route to halt disease progression, pending further validation.