Targeting SUV39H2 Exon Skipping Reversing CDK4/6 Inhibitor Resistance in Breast Cancer [CUT&Tag]

Breast cancer, the most prevalent malignancy among women, is predominantly estrogen receptor-positive (ER+), with ER+ cases accounting for 80% of the total. The combination of CDK4/6 inhibitors and endocrine therapy has become the standard treatment for advanced ER+ breast cancer. However, around 30% of patients exhibit intrinsic resistance, while others eventually develop acquired resistance leading to recurrence and metastasis. Here, we identified reduced exon 2 skipping of SUV39H2 in CDK4/6 inhibitor-resistant breast cancer cells, leading to increased SUV39H2 protein expression and consequent elevation of H3K9me3 levels, collectively suppressing the p53 pathway and promote resistance. Subsequently, we designed antisense oligonucleotides (ASOs) to modulate SUV39H2 exon skipping, which successfully reduced SUV39H2 levels and H3K9me3 modifications, thereby reactivating p53 target genes and restoring drug sensitivity in vitro and in vivo.Our results demonstrate that SUV39H2 serves as both a potential biomarker and therapeutic target for CDK4/6 inhibitor-resistant breast cancer, highlighting its clinical translational value.