美国斯隆凯特林癌症研究所Sarat Chandarlapaty等研究人员合作发现，TP53介导的老年化转换决定乳腺癌对CDK4/6抑制的长期反应。该研究于2024年10月10日在线发表于国际一流学术期刊《癌细胞》。

通过对一大群患有转移性激素受体阳性（HR+）乳腺癌的临床注释队列进行分析，研究人员发现TP53缺失（27.6%）和MDM2扩增（6.4%）与长期疾病控制不足相关。人类乳腺癌模型表明，p53缺失并不改变CDK4/6的活性或G1期阻滞，而是通过CDK2促进对药物不敏感的p130磷酸化。

磷酸化p130的持续存在阻止了DREAM复合体的组装，促使细胞周期重新进入并导致肿瘤进展。CDK2抑制剂可以克服p53的缺失，诱导老年化转换并表现出衰老表型。完全抑制CDK4/6和CDK2激酶对于实现基因组多样的HR+乳腺癌的长期反应是必要的。

据介绍，CDK4/6激酶的抑制在乳腺癌治疗中带来了更好的结果。然而，只有少数患者能够实现长期的疾病控制。

附：英文原文

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

Author: 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 OConnell, Payal Patel, Marie Will, Atsushi Fushimi, Marimar Benitez, Martina Bradic, Li Fan, Harikrishna Nakshatri, Dhivya R. Sudhan, Christopher R. Denz, Jorge S. Reis-Filho, Shom Goel, Andrew Koff, Britta Weigelt, Qamar J. Khan, Pedram Razavi, Sarat Chandarlapaty

Issue&Volume: 2024-10-10

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.

DOI: 10.1016/j.ccell.2024.09.009

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00357-X