确定增强艾瑞布林在三阴性乳腺癌细胞系中抗肿瘤活性的激酶靶点

Identification of Kinase Targets for Enhancing the Antitumor Activity of Eribulin in Triple-Negative Breast Cell Lines.

作者信息

Xie Xuemei, Lee Jangsoon, Fuson Jon A, Liu Huey, Iwase Toshiaki, Yun Kyuson, Margain Cori, Tripathy Debu, Ueno Naoto T

机构信息

Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Research Institute at Houston Methodist, Weill Cornell Medical College, Houston, TX 77030, USA.

出版信息

Biomedicines. 2023 Feb 28;11(3):735. doi: 10.3390/biomedicines11030735.

DOI:10.3390/biomedicines11030735

PMID:36979714

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10045293/

Abstract

BACKGROUND

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype of breast cancer, and current treatments are only partially effective in disease control. More effective combination approaches are needed to improve the survival of TNBC patients. Eribulin mesylate, a non-taxane microtubule dynamics inhibitor, is approved by the U.S. Food and Drug Administration to treat metastatic breast cancer after at least two previous chemotherapeutic regimens. However, eribulin as a single agent has limited therapeutic efficacy against TNBC.

METHODS

High-throughput kinome library RNAi screening, Ingenuity Pathway Analysis, and STRING analysis were performed to identify target kinases for combination with eribulin. The identified combinations were validated using in vivo and ex vivo proliferation assays.

RESULTS

We identified 135 potential kinase targets whose inhibition enhanced the antiproliferation effect of eribulin in TNBC cells, with the PI3K/Akt/mTOR and the MAPK/JNK pathways emerging as the top candidates. Indeed, copanlisib (pan-class I PI3K inhibitor), everolimus (mTOR inhibitor), trametinib (MEK inhibitor), and JNK-IN-8 (pan-JNK inhibitor) produced strong synergistic antiproliferative effects when combined with eribulin, and the PI3K and mTOR inhibitors had the most potent effects in vitro.

CONCLUSIONS

Our data suggest a new strategy of combining eribulin with PI3K or mTOR inhibitors to treat TNBC.

摘要

背景

三阴性乳腺癌（TNBC）是乳腺癌中侵袭性最强的分子亚型，目前的治疗方法在疾病控制方面仅部分有效。需要更有效的联合治疗方法来提高TNBC患者的生存率。甲磺酸艾瑞布林是一种非紫杉烷类微管动力学抑制剂，已获美国食品药品监督管理局批准用于治疗至少接受过两种先前化疗方案后的转移性乳腺癌。然而，艾瑞布林作为单一药物对TNBC的治疗效果有限。

方法

进行高通量激酶组文库RNA干扰筛选、 Ingenuity通路分析和STRING分析，以确定与艾瑞布林联合使用的靶激酶。使用体内和体外增殖试验验证所确定的联合用药方案。

结果

我们鉴定出135个潜在的激酶靶点，抑制这些靶点可增强艾瑞布林对TNBC细胞的抗增殖作用，其中PI3K/Akt/mTOR和MAPK/JNK通路成为最主要的候选通路。事实上，考比替尼（泛I类PI3K抑制剂）、依维莫司（mTOR抑制剂）、曲美替尼（MEK抑制剂）和JNK-IN-8（泛JNK抑制剂）与艾瑞布林联合使用时产生了强烈的协同抗增殖作用，PI3K和mTOR抑制剂在体外具有最显著的效果。