Targeting SUV39H2 exon skipping reverses resistance to CDK4/6 inhibitors via transcriptional activation of p21

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are standard therapies for estrogen receptor–positive breast cancer, but their efficacy is limited by drug resistance. While dysregulation of alternative splicing has been implicated in cancer progression, the underlying mechanisms remain unclear. Here, we uncover a splicing-mediated mechanism whereby exon 2 inclusion in SUV39H2 drives its overexpression in CDK4/6i-resistant breast cancer cells. Clinically, elevated exon 2 inclusion in SUV39H2 correlates with poor prognosis in patients with breast cancer. Targeting SUV39H2 with gapmer antisense oligonucleotides or a methyltransferase inhibitor overcomes CDK4/6i resistance and reinstates therapy-induced senescence in breast cancer cells by reducing SUV39H2 expression or activity. Mechanistically, targeting SUV39H2 promotes transcriptional activation of senescence-associated secretory phenotype genes, including p21 , through H3K9me3 removal at enhancer regions and subsequent chromatin opening at promoters. Our work unveils a splicing-mediated resistance mechanism and presents a potential synergistic drug target for CDK4/6i therapy.