ABL Kinases Regulate Translation in HER2+ Cells through Y-Box-Binding Protein 1 to Facilitate Colonization of the Brain McKernan et al

Human epidermal growth factor receptor 2-positive (HER2/ERBB2) breast cancer patients 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 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.

人类表皮生长因子受体2阳性（HER2/ERBB2）乳腺癌患者常伴发脑转移。HER2靶向疗法治疗脑转移效果不佳，部分原因在于血脑屏障（BBB）穿透性差以及耐药性的产生。本研究报道称，ABL激酶变构抑制剂可改善体内总生存率，并抑制HER2阳性脑转移瘤的生长。从机制上来说，ABL激酶可使RNA结合蛋白Y盒结合蛋白1（YB-1）发生酪氨酸磷酸化。ABL激酶抑制剂会破坏YB-1与ERBB2 mRNA的结合并损害其翻译过程，导致HER2蛋白水平显著降低。ABL依赖的YB-1酪氨酸磷酸化可促进HER2的翻译。值得注意的是，YB-1缺失会抑制脑转移瘤生长，并削弱ABL依赖的脑转移相关靶标子集的表达。上述数据表明，ABL激酶可通过YB-1实现对脑转移靶标的翻译调控，为HER2阳性脑转移患者提供了一个治疗靶点。