文章：

联合PI3K抑制剂与艾日布林在紫杉醇耐药、PIK3CA突变子宫内膜癌临床前模型中增强抗肿瘤活性

Combined PI3K Inhibitor and Eribulin Enhances Anti-Tumor Activity in Preclinical Models of Paclitaxel-Resistant, PIK3CA-Mutated Endometrial Cancer

原文发布日期：8 October 2023

DOI: 10.3390/cancers15194887

类型: Article

开放获取: 是

英文摘要：

Endometrial cancer stands as the predominant gynecological malignancy in developed nations. For advanced or recurrent disease, paclitaxel-based chemotherapy is the standard front-line therapy. However, paclitaxel resistance eternally develops. Based on the high prevalence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, reaching 50%, in endometrial cancer, we preclinically investigated the effectiveness of a combination of a phosphatidylinositol 3-kinase (PI3K) inhibitor with eribulin, a post-paclitaxel therapy for breast cancer, in treating paclitaxel-resistant, PIK3CA-mutated endometrial cancer. We generated paclitaxel-resistant cell lines from PIK3CA-mutated endometrial cancer cell lines by gradually increasing the concentration of paclitaxel in cell cultures. We observed that the PI3K/AKT and epithelial–mesenchymal transition (EMT) pathways in paclitaxel-resistant cells were significantly upregulated compared with those in parental cells. Then, we demonstrated that the combination of alpelisib (a PI3K inhibitor) and eribulin more effectively suppressed the cellular growth of paclitaxel-resistant cells in in vitro and in vivo xenograft models. Mechanistically, we demonstrated that the effect of the combination could be enhanced by inhibiting both the PI3K/AKT and EMT pathways. Therefore, we suggest that paclitaxel resistance is associated with the activation of the PIK3/AKT pathway in PIK3CA-mutated endometrial cancer, and the combination of a PI3K inhibitor and eribulin merits further clinical investigation.

摘要翻译： 

子宫内膜癌是发达国家中最常见的妇科恶性肿瘤。对于晚期或复发性病例，以紫杉醇为基础的化疗是标准的一线治疗方案。然而，紫杉醇耐药性往往随之产生。鉴于子宫内膜癌中磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α（PIK3CA）突变率高达50%，我们通过临床前研究探讨了磷脂酰肌醇3-激酶（PI3K）抑制剂与乳腺癌紫杉醇后线治疗药物艾日布林联合治疗紫杉醇耐药、PIK3CA突变型子宫内膜癌的效果。我们通过逐步增加细胞培养体系中紫杉醇浓度，从PIK3CA突变的子宫内膜癌细胞系中成功构建了紫杉醇耐药细胞系。研究发现，与亲代细胞相比，耐药细胞中PI3K/AKT通路及上皮-间质转化（EMT）通路显著激活。随后通过体外实验及体内移植瘤模型证实，阿培利西（PI3K抑制剂）与艾日布林的联合用药能更有效地抑制紫杉醇耐药细胞的生长。机制研究表明，该联合方案通过同时抑制PI3K/AKT通路和EMT通路增强抗肿瘤效果。因此我们认为，在PIK3CA突变的子宫内膜癌中，紫杉醇耐药性与PI3K/AKT通路激活相关，而PI3K抑制剂与艾日布林的联合治疗方案值得进一步临床研究。

原文链接：

Combined PI3K Inhibitor and Eribulin Enhances Anti-Tumor Activity in Preclinical Models of Paclitaxel-Resistant, PIK3CA-Mutated Endometrial Cancer