From CDK4/6 to CDK2 and KAT: Evolving therapeutic approaches in HR+/HER2– breast cancer

Despite the initial clinical success of CDK4/6 inhibitors in combination with endocrine therapy, the development of resistance (intrinsic and acquired) remains a significant challenge in the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2–) metastatic breast cancer (mBC). Emerging evidence highlights cell cycle reprogramming as a central mechanism of resistance, driven by alterations such as RB1 loss, cyclin E1 overexpression with CDK2 activation, and CDK4/6 upregulation, enabling bypass of CDK4/6 dependency. While additional pathways, including PI3K/AKT/mTOR and FGFR signaling, also contribute, their relative importance varies across tumor contexts. These findings have highlighted the need for next-generation therapeutic approaches aimed at overcoming resistance. Selective targeting of CDK2 and CDK4 represents a promising approach, particularly by inhibiting CDK2-mediated escape mechanisms and improving therapeutic index. Early-phase clinical trials have shown encouraging activity, although evidence remains limited. Beyond cell cycle kinases, epigenetic regulators such as lysine acetyltransferases (KATs) have emerged as novel therapeutic targets, with the potential to restore endocrine sensitivity and modulate oncogenic transcriptional programs. In parallel, AURKA inhibitors are being explored to target cell cycle reprogramming associated with resistance. This review focuses on cell cycle–centric mechanisms of resistance to CDK4/6 inhibitors, with particular emphasis on CDK2/CDK4-directed strategies and emerging epigenetic approaches such as KAT inhibition.