Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion

Abstract

Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a large, clinically annotated cohort of patients with metastatic hormone receptor-positive (HR+) breast cancer, we identify TP53 loss (27.6%) and MDM2 amplification (6.4%) to be associated with lack of long-term disease control. Human breast cancer models reveal that p53 loss does not alter CDK4/6 activity or G1 blockade but instead promotes drug-insensitive p130 phosphorylation by CDK2. The persistence of phospho-p130 prevents DREAM complex assembly, enabling cell-cycle re-entry and tumor progression. Inhibitors of CDK2 can overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically diverse HR+ breast cancers. • TP53 mutation is associated with lack of long-term disease control on CDK4/6i • p53 deficiency suppresses DREAM complex in BC cells, enabling cell-cycle re-entry • Disruption of DREAM complex is sufficient to promote long-term CDK4/6i resistance • Inhibition of CDK2 overcomes p53 loss, promoting geroconversion and disease control Kudo et al. demonstrate that TP53 loss in HR+ breast cancer is clinically associated with long-term failure of CDK4/6i due to cellular escape from quiescence via impaired DREAM complex assembly. Selective CDK2 inhibition is found to reinforce p130 dephosphorylation in p53 mutant models and facilitate durable tumor growth suppression.