Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSK), New York, NY 10065, USA; Department of Surgery, The Jikei University School of Medicine, Tokyo 1058461, Japan.
Breast Medicine Service, Department of Medicine, MSK, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
Cancer Cell. 2024 Nov 11;42(11):1919-1935.e9. doi: 10.1016/j.ccell.2024.09.009. Epub 2024 Oct 10.
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.
CDK4/6 激酶抑制已导致乳腺癌患者的预后得到改善。然而，只有少数患者能够长期控制疾病。我们使用了一个大型的、具有临床注释的转移性激素受体阳性（HR+）乳腺癌患者队列，发现 TP53 缺失（27.6%）和 MDM2 扩增（6.4%）与缺乏长期疾病控制相关。人类乳腺癌模型显示，p53 缺失不会改变 CDK4/6 的活性或 G1 阻滞，但会通过 CDK2 促进药物不敏感的 p130 磷酸化。磷酸化 p130 的持续存在阻止了 DREAM 复合物的组装，从而使细胞周期重新进入并促进肿瘤进展。CDK2 抑制剂可以克服 p53 缺失，导致衰老转化和衰老表型的表现。似乎需要完全抑制 CDK4/6 和 CDK2 激酶才能促进具有不同基因组的 HR+乳腺癌的长期反应。
