Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion
Journal Title
Cancer Cell
Publication Type
Online publication before print
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.
Keywords
Cdk2; Cdk4/6; breast cancer; cell cycle; cyclin dependent kinase; drug resistance; p53; quiescence; senescence
Department(s)
Medical Oncology
Open Access at Publisher's Site
https://doi.org/10.1016/j.ccell.2024.09.009
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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