The Landscape of Glycogen synthase kinase-3 beta (GSK-3b) Genomic Alterations in Cancer.

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Molecular cancer therapeutics




Glycogen synthase kinase-3B (GSK-3B), a serine/threonine kinase, has been implicated in the pathogenesis of many cancers, with involvement in cell cycle regulation, apoptosis, and immune response. Small molecule GSK-3B inhibitors are currently undergoing clinical investigation. Tumor sequencing has revealed genomic alterations in GSK-3B, yet an assessment of the genomic landscape in malignancies is lacking. This study assessed >100,000 tumors from two databases to analyze GSK-3B alterations. GSK-3B expression and immune cell infiltrate data was analyzed across cancer types, and PD-L1 expression was compared between GSK-3B-mutated and wild-type tumors. GSK-3B was mutated at a rate of 1%. The majority of mutated residues were in the kinase domain, with frequent mutations occurring in a GSK-3B substrate binding pocket. Uterine endometrioid carcinoma was the most commonly mutated (4%) tumor, and copy number variations (CNVs) were most commonly observed in squamous histologies. Significant differences across cancer types for GSK-3B-mutated tumors were observed for B cells (p=0.018), monocytes (p=0.002), dendritic cells (p=0.005), neutrophils (p=0.0003), and endothelial cells(p=0.014). GSK-3B mRNA expression was highest in melanoma. The frequency of PD-L1 expression was higher among GSK-3B-mutated tumors compared to wild-type in colorectal cancer(p=0.03), endometrial cancer(p=0.05), melanoma(p=0.02), ovarian carcinoma(p=0.0001), and uterine sarcoma(p=0.002). Overall, GSK-3B molecular alterations were detected in approximately 1% of solid tumors, tumors with GSK-3B mutations displayed a microenvironment with increased infiltration of B cells, and GSK-3B mutations were associated with increased PD-L1 expression in selected histologies. These results advance the understanding of GSK-3B complex signaling network interfacing with key pathways involved in carcinogenesis and immune response.

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