Interrogating Transcriptional and Translational Networks that Promote Metastatic Colonization of the Brain

Human epidermal growth factor receptor 2-positive (HER2+) and triple-negative 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. Notably, there is a lack of effective FDA-approved targeted therapies for patients with triple-negative breast cancer brain metastases. Here we explore the transcriptional and translational networks that drive breast cancer brain metastasis.

We report that ABL kinase allosteric inhibitors improve overall survival and impair HER2+ brain metastatic burden in vivo. ABL kinase inhibition leads to a profound decrease in HER2 protein levels in HER2+ brain metastatic cells. Mechanistically, ABL kinases regulate translation of HER2/ERBB2 through the RNA binding protein Y-box-binding protein 1 (YB-1). YB-1 crosslinking immunoprecipitation (CLIP)-sequencing and RNA immunoprecipitation of YB-1 revealed YB-1 binds to ERBB2 and a subset of mRNAs linked to brain metastasis. Loss of YB-1 inhibits brain metastatic outgrowth and impairs expression of a subset of ABL-dependent brain metastatic targets. These data support a previously unknown role for ABL kinases in the translational regulation of brain metastatic targets through YB-1 and offer a new therapeutic target for HER2+ brain metastasis patients. To characterize the transcriptional landscape of human brain metastases, spatial transcriptomics was performed on patient samples. Analysis of the tumor and surrounding brain microenvironment may identify novel vulnerabilities that could translate into therapies for patients with brain metastases.