Mechanisms underlying drug resistance to GSK126, an EZH2 inhibitor, in a human melanoma cell line

Enhancer of zeste homolog 2 (EZH2), a catalytic subunit within the polycomb repressive complex 2 (PRC2), is associated with increased trimethylation at histone 3 lysine 27 (H3K27me3) leading to gene silencing. EZH2 has been implicated in the pathogenesis of tumorigenesis, drug resistance, and tumor immunosuppression, and its upregulation has been observed across various malignancies including prostate cancer, breast cancer, gastric cancer, anaplastic thyroid carcinoma, nasopharyngeal carcinoma, and endometrial carcinoma.Despite the development of numerous EZH2 inhibitors, only EPZ-6438 has obtained clinical approval, however, GSK126 (GSK2816126), another highly selective EZH2 inhibitor, exhibited inefficacy in suppressing tumor growth during clinical trials. Experiments demonstrated that GSK126 effectively inhibits tumor growth in immunodeficient mice, while exhibiting no discernible impact on tumors in immunocompetent mice. Notably, GSK126 induces an aggressive immunosuppressive tumor microenvironment by promoting the differentiation of hematopoietic progenitor cells into myeloid-derived suppressor cells (MDSCs) and suppressing the differentiation of type 1 macrophages. These findings suggest that GSK126 may potentially contribute to tumor immunosuppression, thereby attenuating its own antitumor efficacy; however, the precise underlying mechanism remains to be elucidated.