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10/10/2024

Long-Term Breast Cancer Response to CDK4/6 Inhibition Defined by TP53-Mediated Geroconversion

Cancer Cell Manuscript
Authors Rei Kudo, Anton Safonov, Catherine Jones, Enrico Moiso, Jonathan R. Dry, Hong Shao, Sharanya Nag, Edaise M. da Silva, Selma Yeni Yildirim, Qing Li, Elizabeth O'Connell, Payal Patel, Marie Will, Atsushi Fushimi, Marimar Benitez, Martina Bradic, Li Fan, Harikrishna Nakshatri, Dhivya R. Sudhan, Christopher R. Denz, Iker Huerga Sanchez, Jorge S. Reis-Filho, Shom Goel, Andrew Koff, Britta Weigelt, Qamar J. Khan, Pedram Razavi, and Sarat Chandarlapaty

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.

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