| Autor: |
Courtney M. McKernan, Aaditya Khatri, Molly Hannigan, Jessica Child, Qiang Chen, Benjamin Mayro, David Snyder, Christopher V. Nicchitta, Ann Marie Pendergast |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Cell reports. 40(9) |
| ISSN: |
2211-1247 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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