School of Graduate Studies, SUNY Downstate Medical Center, Brooklyn, New York.
Departments of Pediatrics and Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York.
Mol Cancer Res. 2018 Mar;16(3):361-377. doi: 10.1158/1541-7786.MCR-17-0602. Epub 2018 Jan 12.
Cyclin-dependent kinase 4/6 (CDK4/6)-specific inhibitors, such as palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4. p27Kip1 is a required assembly factor for cyclin-CDK4 complexes, but it must be phosphorylated on residue Y88 to open or activate the complex. The Brk-SH3 peptide, ALT, blocks p27 Y88 phosphorylation, inhibiting CDK4. Nonphosphorylated p27 is no longer a target for ubiquitin-mediated degradation and this stabilized p27 now also inhibits CDK2 activity. Thus, ALT induction inhibits both the kinase that drives proliferation (CDK4) and the kinase that mediates resistance (CDK2), causing a potent and long-lasting cell-cycle arrest. ALT arrests growth of all breast cancer subgroups and synergizes with palbociclib to increase cellular senescence and to cause tumor regression in breast cancer xenograft models. The use of ALT demonstrates that both CDK4 and CDK2 need to be inhibited if long-term efficacy is to be achieved and represents a novel modality to inhibit breast cancer cells. Modulating tyrosine phosphorylation of p27 impacts both proliferative (CDK4) and resistance (CDK2) mechanisms in breast cancer and suggests that phospho-p27 status may serve as a biomarker for patients that are responsive to CDK4/6 inhibition. .
细胞周期蛋白依赖性激酶 4/6（CDK4/6）-特异性抑制剂，如帕博西利，已显示出临床疗效，但已出现原发性或继发性耐药。为了开发更有效的治疗方法，需要研究耐药或适应的机制。在这里，研究表明 CDK2 代偿 CDK4 活性的丧失以挽救帕博西利阻滞的乳腺癌细胞，这表明需要抑制两种激酶以实现持久的反应。此外，还描述了一种抑制酪氨酸磷酸化 p27Kip1（CDKN1B）并同时抑制 CDK2 和 CDK4 的新策略。p27Kip1 是细胞周期蛋白-CDK4 复合物的必需组装因子，但它必须在残基 Y88 上磷酸化才能打开或激活复合物。Brk-SH3 肽，ALT，阻断 p27 Y88 磷酸化，抑制 CDK4。非磷酸化的 p27 不再是泛素介导的降解的靶标，这种稳定的 p27 现在也抑制 CDK2 活性。因此，ALT 诱导抑制驱动增殖的激酶（CDK4）和介导耐药的激酶（CDK2），导致强烈和持久的细胞周期阻滞。ALT 阻滞所有乳腺癌亚组的生长，并与帕博西利协同作用，增加细胞衰老并导致乳腺癌异种移植模型中的肿瘤消退。ALT 的使用表明，如果要实现长期疗效，则需要抑制 CDK4 和 CDK2，并且代表了一种抑制乳腺癌细胞的新方法。调节 p27 的酪氨酸磷酸化会影响乳腺癌中的增殖（CDK4）和耐药（CDK2）机制，并表明磷酸化 p27 状态可能作为对 CDK4/6 抑制有反应的患者的生物标志物。
