通过 Rb 降解和 c-Myc 依次激活 E2F 可驱动乳腺癌对 CDK4/6 抑制剂的耐药性。
Sequential activation of E2F via Rb degradation and c-Myc drives resistance to CDK4/6 inhibitors in breast cancer.
发表日期：2023 Oct 21
作者：
Sungsoo Kim, Jessica Armand, Anton Safonov, Mimi Zhang, Rajesh K Soni, Gary Schwartz, Julia E McGuinness, Hanina Hibshoosh, Pedram Razavi, Minah Kim, Sarat Chandarlapaty, Hee Won Yang
来源：
Cell Reports
摘要：
细胞周期蛋白依赖性激酶 4 和 6 抑制剂 (CDK4/6i) 是治疗转移性激素受体阳性乳腺癌的关键治疗药物。然而，耐药性的出现限制了它们的长期疗效。在这里，我们表明乳腺癌细胞通过 E2F 激活的连续两步过程产生 CDK4/6i 耐药性。该过程需要视网膜母细胞瘤 (Rb) 蛋白降解，然后是 c-Myc 介导的 E2F 转录活性放大。 CDK4/6i 治疗以 Rb 依赖性方式停止细胞增殖，但显着降低 Rb 蛋白水平。然而，Rb 水平的降低不足以诱导 E2F 活性。为了产生 CDK4/6i 抗性，需要上调或激活促有丝分裂或激素信号传导的突变来稳定 c-Myc 水平，从而增强 E2F 活性。我们对治疗前肿瘤样本的分析揭示了 c-Myc 水平（而不是 Rb 水平）与 CDK4/6i 治疗后不良治疗结果之间存在很强的相关性。此外，我们提出蛋白酶体抑制剂可以通过恢复 Rb 水平来逆转 CDK4/6i 耐药性。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are key therapeutic agents in the management of metastatic hormone-receptor-positive breast cancer. However, the emergence of drug resistance limits their long-term efficacy. Here, we show that breast cancer cells develop CDK4/6i resistance via a sequential two-step process of E2F activation. This process entails retinoblastoma (Rb)-protein degradation, followed by c-Myc-mediated amplification of E2F transcriptional activity. CDK4/6i treatment halts cell proliferation in an Rb-dependent manner but dramatically reduces Rb-protein levels. However, this reduction in Rb levels insufficiently induces E2F activity. To develop CDK4/6i resistance, upregulation or activating mutations in mitogenic or hormone signaling are required to stabilize c-Myc levels, thereby augmenting E2F activity. Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.