乳腺癌对 CDK4/6 抑制的长期反应由 TP53 介导的老年转化定义。
Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion.
发表日期：2024 Oct 04
作者：
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, Jorge S Reis-Filho, Shom Goel, Andrew Koff, Britta Weigelt, Qamar J Khan, Pedram Razavi, Sarat Chandarlapaty
来源：
CANCER CELL
摘要：
CDK4/6 激酶的抑制可改善乳腺癌的预后。然而，只有少数患者的疾病得到长期控制。通过使用大量经过临床注释的转移性激素受体阳性 (HR) 乳腺癌患者队列，我们发现 TP53 丢失 (27.6%) 和 MDM2 扩增 (6.4%) 与缺乏长期疾病控制有关。人类乳腺癌模型表明，p53 缺失不会改变 CDK4/6 活性或 G1 阻断，而是促进 CDK2 对药物不敏感的 p130 磷酸化。磷酸化 p130 的持续存在可阻止 DREAM 复合物组装，从而实现细胞周期重新进入和肿瘤进展。 CDK2 抑制剂可以克服 p53 丢失，导致老年转化和衰老表型的表现。完全抑制 CDK4/6 和 CDK2 激酶似乎对于促进基因组多样化 HR 乳腺癌的长期缓解是必要的。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。
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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.