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.