The clinical efficacy of CDK2 inhibition in CDK4/6 inhibitor-resistant HR-positive breast cancer is dependent on p53 but independent of RB

Patients with hormone receptor-positive metastatic breast cancer (HR+MBC) eventually progress on CDK4/6 inhibition therapy, underscoring an unmet need for novel targeted therapies. The emergence of selective CDK2 inhibitors presents a promising advancement, positioning these agents for early clinical evaluation. Here, we analyzed tumor and liquid biopsies from patients treated with PF-07104091, the most clinically advanced CDK2 inhibitor. CDK2 inhibition monotherapy proved effective in CDK4/6 inhibitor-resistant HR+MBC patients lacking TP53 mutations. Studies in patient-derived cell lines confirmed that CDK2 inhibition efficacy is p53-dependent but unexpectedly revealed its independence from RB. Notably, we observed increased sensitivity to CDK2 inhibition in models resistant to CDK4/6 inhibitors. Unlike CDK4/6 inhibitors, CDK2 inhibition does not activate RB but rather targets DNA replication, accumulating cells in G2/M. Our findings unravel a novel mechanism of cell cycle arrest mediated through CDK2 and advocate the clinical development of CDK2 inhibitors to address resistance to CDK4/6 therapies in HR+MBC.