The Louis V. Gerstner Graduate School of Biomedical Science, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
The Programs in MolecularMemorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
Oncogene. 2018 Sep;37(37):5066-5078. doi: 10.1038/s41388-018-0332-y. Epub 2018 May 23.
CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated and dedifferentiated liposarcoma their clinical promise is associated with their ability to downregulate the MDM2 protein. The downregulation of MDM2 following treatment with CDK4/6 inhibitors also induces many cultured tumor cell lines derived from different types of malignancies to progress from quiescence into senescence. Here we used cultured human cell lines and defined a role for PDLIM7 and CDH18, regulating MDM2 protein in CDK4/6 inhibitor-treated cells. Materials from our previous phase II trials with palbociclib were then used to demonstrate that expression of CDH18 protein was associated with response, measured as both progression-free survival and overall survival. This supports the hypothesis that the biologic transition from quiescence to senescence has clinical relevance for this class of drugs.
CDK4/6 抑制剂被用于治疗多种人类恶性肿瘤。在高分化和去分化脂肪肉瘤中，它们的临床应用前景与其下调 MDM2 蛋白的能力有关。CDK4/6 抑制剂治疗后 MDM2 的下调也诱导许多来自不同类型恶性肿瘤的培养肿瘤细胞系从静止期进入衰老期。在这里，我们使用培养的人细胞系，并确定了 PDLIM7 和 CDH18 在 CDK4/6 抑制剂处理的细胞中调节 MDM2 蛋白的作用。然后，我们使用来自以前的 palbociclib 二期临床试验的材料来证明 CDH18 蛋白的表达与反应相关，这可以通过无进展生存期和总生存期来衡量。这支持了这样一种假设，即从静止期到衰老期的生物学转变对这类药物具有临床意义。
