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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • McKernan, CM; Khatri, A; Hannigan, M; Child, J; Chen, Q; Mayro, B; Snyder, D; Nicchitta, CV; Pendergast, AM

Published Date

  • August 30, 2022

Published In

Volume / Issue

  • 40 / 9

Start / End Page

  • 111268 -

PubMed ID

  • 36044842

Pubmed Central ID

  • PMC9472557

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2022.111268

Language

  • eng

Conference Location

  • United States