Duan, N.; Hua, Y.; Zhou, Z.; Jin, N.; Li, W.; Yin, Y.

Primary trastuzumab resistance remains a major challenge in the treatment of HER2-positive breast cancer, with limited therapeutic options highlighting the need for deeper mechanistic insight. Here, integrative analysis of epigenomic and three-dimensional chromatin architecture reveals widespread remodeling of the regulatory landscape in resistant cells. Alterations in promoter-associated histone modifications?particularly H3K4me3 and H3K27me3?together with changes in active enhancer activity and promoter-enhancer interactions, appear to be key drivers of transcriptional reprogramming underlying resistance. As an illustrative example, SGK1 exhibits epigenetic activation in resistant cells, characterized by increased promoter H3K4me3 and enhanced chromatin interactions, consistent with its role in supporting cell survival, proliferation and metastasis. Overall, our findings highlight epigenetic and chromatin structural alterations as central mechanisms of primary trastuzumab resistance, providing a framework for novel therapeutic strategies development.