Oncology Unit, 3rd Department of Medicine, 'Sotiria' General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Mol Biol Rep. 2021 Jan;48(1):915-925. doi: 10.1007/s11033-020-06100-3. Epub 2021 Jan 7.
Cyclin-dependent kinase (CDK) 4/6 inhibitors have emerged in the treatment of metastatic hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, most patients will eventually present disease progression, highlighting the inevitable resistance of cancer cells to CDK4/6 inhibition. Several studies have suggested that resistance mechanisms involve aberrations of the molecules that regulate the cell cycle, and the re-wiring of the cell to escape CDK4/6 dependence and turn to alternative pathways. Loss of retinoblastoma function, overexpression of CDK 6, upregulation of cyclin E, overexpression of CDK 7, and dysregulation of several signaling pathways, notably the PI3/AKT/mTOR pathway, have been implicated in the development of resistance to CDK4/6 inhibitors. Overlap with endocrine resistance mechanisms might be possible. Combinational therapeutic strategies should be explored in order to prevent resistance and optimize the management of patients after progression under CDK 4/6 inhibition.
细胞周期蛋白依赖性激酶（CDK）4/6 抑制剂已应用于治疗转移性激素受体（HR）阳性和人表皮生长因子受体 2（HER2）阴性乳腺癌。然而，大多数患者最终会出现疾病进展，这突显了癌细胞对 CDK4/6 抑制的不可避免的耐药性。几项研究表明，耐药机制涉及调节细胞周期的分子异常，以及细胞重新布线以逃避 CDK4/6 依赖性并转向替代途径。视网膜母细胞瘤功能丧失、CDK6 过表达、细胞周期蛋白 E 上调、CDK7 过表达以及几种信号通路（尤其是 PI3/AKT/mTOR 通路）的失调与 CDK4/6 抑制剂耐药的发展有关。可能存在与内分泌耐药机制的重叠。应该探索联合治疗策略，以防止耐药，并在 CDK4/6 抑制后进展的情况下优化患者的管理。
