BSBM-04 Tyrosine Kinase-Dependent Networks in Brain Metastasis Reveal Actionable Therapeutic Targets

Brain metastases are the most common intracranial tumors in adults and are associated with increased patient morbidity and mortality. Limited therapeutic options are currently available for the treatment of brain metastasis. We reported that ABL kinase-dependent regulation of transcription factor networks targeting the Heat Shock Factor 1 (HSF1) and the TAZ co-activator are required for lung cancer metastasis to the brain. We have uncovered a novel pathway whereby ABL kinases promote translation of oncogenic proteins in Human epidermal growth factor receptor 2-positive (HER2+) breast cancer cells. We found that ABL kinase allosteric inhibitors improve overall survival and impair HER2+ brain metastatic outgrowth in vivo. Mechanistically, ABL kinase inhibition disrupts interaction of RNA-binding proteins to the HER2/ERBB2 mRNA and impairs translation, leading to a profound decrease in HER2 protein levels. Crosslinking immunoprecipitation (CLIP)-sequencing and RNA immunoprecipitation revealed ABL-regulated interactions of RNA-binding proteins to ERBB2 and a subset of mRNAs linked to brain metastasis. We found that ABL kinases form a complex with and phosphorylate RNA-binding proteins, which is required for efficient translation and expression of the HER2 protein. Notably, depletion of ABL-regulated RNA-binding proteins impairs brain tumor burden and improves overall survival of tumor-bearing mice. These data support a previously unknown role for ABL kinases in the translational regulation of brain metastatic targets through RNA-binding proteins and translational regulation. Inhibition of these networks may underlie in part the observed therapeutic effectiveness of ABL-specific allosteric inhibitors, which we found impair outgrowth and colonization of HER2+ breast cancer cells in the brain of mice harboring these tumors.