Abstract P3-03-04: Role of ABL kinase signaling in metastatic breast cancer colonization of the brain

Abstract

Abstract Breast cancer brain metastasis (BCBM) occurs in approximately 50% of late-stage Human Epidermal Growth Factor Receptor 2-positive (HER2+) breast cancer patients. BCBM may result in cognitive decline and cranial neuropathies and is associated with a median survival rate of nine months. Current therapies for BCBM, such as whole brain radiation therapy, can enhance cognitive impairment while targeted therapies and chemotherapy are ineffective. Despite the increased patient survival due to HER2 targeted therapies, patients often relapse due to brain metastases. Recently, our laboratory has discovered a role for Abelson (Abl) family of tyrosine kinases, ABL1 and ABL2, in breast cancer metastasis. Evaluation of 279 HER2+ breast cancer patients demonstrates a correlation between high expression of ABL1 and decreased distant metastasis free survival. Expression of ABL1 and ABL2 increase in brain metastatic breast cancer cells compared to parental cells, suggesting a role for the Abl kinases in breast cancer brain metastasis. I have found that treatment with the allosteric Abl kinase inhibitor GNF5 decreases colonization of the brain by two distinct human HER2+ breast cancer cell lines. Increasing evidence suggests that HER2 is upregulated in breast cancer cells colonizing the brain and may interact with the brain microenvironment to promote outgrowth. Both pharmacologic and genetic inhibition of the Abl kinases decreases HER2 protein expression in brain metastatic HER2+ breast cancer cells, potentially ablating the cell’s ability to proliferate in the brain. These data support a role for Abl kinases in promoting colonization of the brain by breast cancer cells. Due to its blood-brain barrier penetrance and efficacy in pre-clinical mouse models, Abl kinase-specific allosteric inhibitors may provide a novel therapeutic strategy for HER2+ breast cancer brain metastasis. Citation Format: Courtney Michelle McKernan, Ann M Pendergast. Role of ABL kinase signaling in metastatic breast cancer colonization of the brain [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-04.