文章：

CDK4/6抑制剂通过RBM38 RNA结合蛋白抑制突变型P53表达，从而抑制RB缺失型三阴性乳腺癌

CDK4/6 Inhibitors Suppress RB-Null Triple-Negative Breast Cancer by Inhibiting Mutant P53 Expression via RBM38 RNA-Binding Protein

原文发布日期：16 October 2025

DOI: 10.3390/cancers17203339

类型: Article

开放获取: 是

英文摘要：

Background:Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been developed and clinically used as a frontline targeted therapeutic agent for hormone receptor-positive (HR+), HER2-negative breast cancer. However, the efficacy for CDK4/6 inhibitors varies in different types of cancer and thus there is a need to identify new biomarkers that would help predict efficacy and/or resistance.Methods:We examined the effect of CDK4/6 inhibitors in both RB-proficient and -deficient triple-negative breast cancer (TNBC) cells. We also examined whether mutant p53 could be a target and/or prognostic marker for CDK4/6 inhibitors in (TNBC).Results:We found that CDK4/6 inhibitors suppress mutant p53 expression in both RB-proficient and RB-deficient TNBC cells. We also found that suppression of mutant p53 is responsible for CDK4/6 inhibitors suppressing TNBC cell survival. Mechanistically, we showed that CDK4/6 inhibitors suppress mutant p53 mRNA translation through the RNA-binding protein RBM38. Previously, we showed that when phosphorylated at serine 195, phosphorylated RBM38 interacts with eIF4G on p53 mRNA and promotes p53 mRNA translation. Indeed, we found that CDK4 phosphorylates RBM38 at serine 195, which subsequently enhances mutant p53 mRNA translation.Conclusions:Collectively, our findings suggest that mutant p53 could serve as a potential biomarker for the therapeutic efficacy of CDK4/6 inhibitors.

摘要翻译： 

背景：细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂已被开发并临床用作激素受体阳性（HR+）、HER2阴性乳腺癌的一线靶向治疗药物。然而，CDK4/6抑制剂在不同类型癌症中的疗效存在差异，因此需要寻找新的生物标志物以帮助预测疗效和/或耐药性。 方法：我们在RB功能正常与缺失的三阴性乳腺癌（TNBC）细胞中检测了CDK4/6抑制剂的作用，并探讨了突变型p53是否可能成为CDK4/6抑制剂在三阴性乳腺癌中的治疗靶点和/或预后标志物。 结果：研究发现，CDK4/6抑制剂在RB功能正常与缺失的TNBC细胞中均能抑制突变型p53的表达。同时，抑制突变型p53是CDK4/6抑制剂降低TNBC细胞存活率的关键机制。从分子机制上，我们证实CDK4/6抑制剂通过RNA结合蛋白RBM38抑制突变型p53的mRNA翻译。前期研究表明，当RBM38在丝氨酸195位点发生磷酸化后，磷酸化RBM38可与p53 mRNA上的eIF4G相互作用并促进p53 mRNA翻译。本研究发现CDK4能在丝氨酸195位点磷酸化RBM38，进而增强突变型p53的mRNA翻译。 结论：综合而言，我们的研究结果表明突变型p53可能作为CDK4/6抑制剂治疗效果的潜在生物标志物。

原文链接：

CDK4/6 Inhibitors Suppress RB-Null Triple-Negative Breast Cancer by Inhibiting Mutant P53 Expression via RBM38 RNA-Binding Protein