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

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2024-10-10 DOI:10.1016/j.ccell.2024.09.009

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, Sarat Chandarlapaty

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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.

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由 TP53 介导的雌激素转化确定乳腺癌对 CDK4/6 抑制的长期反应

抑制 CDK4/6 激酶可改善乳腺癌的治疗效果。然而，只有少数患者的病情得到了长期控制。通过对大量激素受体阳性（HR+）转移性乳腺癌患者进行临床注释，我们发现 TP53 缺失（27.6%）和 MDM2 扩增（6.4%）与缺乏长期疾病控制有关。人类乳腺癌模型显示，P53 的缺失不会改变 CDK4/6 的活性或 G1 阻断，反而会促进 CDK2 对药物不敏感的 p130 磷酸化。磷酸化 p130 的持续存在阻止了 DREAM 复合物的组装，使细胞周期再入和肿瘤进展成为可能。CDK2 抑制剂可以克服 p53 的缺失，导致老年转化和衰老表型的表现。完全抑制 CDK4/6 和 CDK2 激酶似乎是促进不同基因组 HR+ 乳腺癌长期应答的必要条件。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.