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). Recent advances have shed light on resistance mechanisms that primarily affect the cell cycle machinery, including loss of Rb function, cyclin E1 overexpression leading to CDK2 activation, and CDK6 or CDK4 upregulation. These alterations disrupt the G1/S checkpoint and drive proliferation independently of CDK4/6 inhibition. In contrast, non-cell cycle-related pathways, such as PI3K/AKT/mTOR and FGFR signaling, may also contribute but appear less central in many resistant tumors. These findings have highlighted the need for next-generation therapeutic approaches aimed at overcoming resistance. Selective inhibition of CDK2 and/or CDK4 is among the most promising strategies, potentially offering a more favorable therapeutic index while maintaining anti-proliferative efficacy. Early-phase trials of selective CDK2/CDK4 inhibitors, alone or combined, have shown encouraging activity, particularly in tumors resistant to prior CDK4/6 inhibition. However, most available data are limited to small, selected cohorts, underscoring the need for larger, randomized studies. Another emerging approach targets lysine acetyltransferases (KAT), key epigenetic regulators of transcription and cancer progression. KAT inhibition has shown potential to modulate oncogenic signaling and sensitize tumor cells to existing therapies, offering a complementary avenue for overcoming resistance. This review focuses on emerging cell cycle-centric mechanisms of resistance to CDK4/6 inhibitors and highlights innovative therapeutic strategies aimed at improving outcomes in HR+/HER2- mBC.