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ABL 激酶通过 Y 盒结合蛋白 1 调节 HER2+ 细胞中的翻译，从而促进脑定植。

ABL kinases regulate translation in HER2+ cells through Y-box-binding protein 1 to facilitate colonization of the brain.

机构信息

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.

出版信息

Cell Rep. 2022 Aug 30;40(9):111268. doi: 10.1016/j.celrep.2022.111268.

DOI:10.1016/j.celrep.2022.111268
PMID:36044842
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9472557/
Abstract

Patients with human epidermal growth factor receptor 2-positive (HER2+/ERBB2) breast cancer often present with brain metastasis. HER2-targeted therapies have not been successful to treat brain metastases in part due to poor blood-brain barrier (BBB) penetrance and emergence of resistance. Here, we report that Abelson (ABL) kinase allosteric inhibitors improve overall survival and impair HER2+ brain metastatic outgrowth in vivo. Mechanistically, ABL kinases phosphorylate the RNA-binding protein Y-box-binding protein 1 (YB-1). ABL kinase inhibition disrupts binding of YB-1 to the ERBB2 mRNA and impairs translation, leading to a profound decrease in HER2 protein levels. ABL-dependent tyrosine phosphorylation of YB-1 promotes HER2 translation. Notably, loss of YB-1 inhibits brain metastatic outgrowth and impairs expression of a subset of ABL-dependent brain metastatic targets. These data support a role for ABL kinases in the translational regulation of brain metastatic targets through YB-1 and offer a therapeutic target for HER2+ brain metastasis patients.

摘要

人表皮生长因子受体 2 阳性（HER2+/ERBB2）乳腺癌患者常发生脑转移。HER2 靶向治疗未能成功治疗脑转移，部分原因是血脑屏障（BBB）通透性差和耐药性的出现。在这里，我们报告 Abelson（ABL）激酶变构抑制剂可改善整体存活率，并损害体内 HER2+脑转移的生长。从机制上讲，ABL 激酶磷酸化 RNA 结合蛋白 Y 盒结合蛋白 1（YB-1）。ABL 激酶抑制破坏了 YB-1 与 ERBB2 mRNA 的结合，并损害翻译，导致 HER2 蛋白水平的显著降低。ABL 依赖性 YB-1 酪氨酸磷酸化促进 HER2 翻译。值得注意的是，YB-1 的缺失抑制脑转移生长，并损害一组 ABL 依赖性脑转移靶标。这些数据支持 ABL 激酶通过 YB-1 参与脑转移靶标的翻译调控，并为 HER2+脑转移患者提供了治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/2709a3b9abc6/nihms-1833559-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/4d3c92434b75/nihms-1833559-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/25a10585b4b7/nihms-1833559-f0003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/7a6a39bdb22f/nihms-1833559-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/82716de9a02c/nihms-1833559-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/2709a3b9abc6/nihms-1833559-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/4d3c92434b75/nihms-1833559-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/25a10585b4b7/nihms-1833559-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/1ac254554e83/nihms-1833559-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/26b0434b0783/nihms-1833559-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/7a6a39bdb22f/nihms-1833559-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/82716de9a02c/nihms-1833559-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bdb8/9472557/2709a3b9abc6/nihms-1833559-f0008.jpg

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