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

Kudo, R; Safonov, A; Jones, C; Moiso, E; Dry, JR; Shao, H; Nag, S; da Silva, EM; Yildirim, SY; Li, Q; O&#39;Connell, E; Patel, P; Will, M; Fushimi, A; Benitez, M; Bradic, M; Fan, L; Nakshatri, H; Sudhan, DR; Denz, CR; Huerga Sanchez, I; Reis-Filho, JS; Goel, S; Koff, A; Weigelt, B; Khan, QJ; Razavi, P; Chandarlapaty, S

Author(s): Kudo, R; Safonov, A; Jones, C; Moiso, E; Dry, JR; Shao, H; Nag, S; da Silva, EM; Yildirim, SY; Li, Q; O'Connell, E; Patel, P; Will, M; Fushimi, A; Benitez, M; Bradic, M; Fan, L; Nakshatri, H; Sudhan, DR; Denz, CR; Huerga Sanchez, I; Reis-Filho, JS; Goel, S; Koff, A; Weigelt, B; Khan, QJ; Razavi, P; Chandarlapaty, S;
Details: Publication Year 2024-11-11,Volume 42,Issue #11,Page 1919-1935
Journal Title: Cancer Cell
Publication Type: Research article
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.
Publisher: Cell Press
Keywords: Humans; *Breast Neoplasms/drug therapy/genetics/pathology/metabolism; *Cyclin-Dependent Kinase 6/antagonists & inhibitors/metabolism; *Cyclin-Dependent Kinase 4/antagonists & inhibitors/metabolism; Female; *Tumor Suppressor Protein p53/metabolism/genetics; *Cyclin-Dependent Kinase 2/metabolism; Cell Line, Tumor; Phosphorylation; Animals; Protein Kinase Inhibitors/pharmacology/therapeutic use; Proto-Oncogene Proteins c-mdm2/metabolism/antagonists & inhibitors/genetics; Cellular Senescence/drug effects; Mice; Cdk2; Cdk4/6; breast cancer; cell cycle; cyclin dependent kinase; drug resistance; p53; quiescence; senescence
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1016/j.ccell.2024.09.009
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.

Creation Date: 2024-12-17 03:14:01

Last Modified: 2024-12-17 03:15:01