Abstract
Brain metastases are a common consequence of advanced lung and breast cancer resulting in functional impairment, cranial neuropathies, and decline in quality of life. Current therapies for brain metastasis, such as whole brain radiation therapy, can result in cognitive impairment, while targeted therapies and chemotherapy are largely ineffective due, in part, to the emergence of resistance and inability to reach effective concentrations in the central nervous system (CNS). We have uncovered a role for the Abelson (ABL) family of tyrosine kinases, ABL1 and ABL2, in lung and breast cancer metastasis to the brain. We show that cancer cells increase ABL expression upon colonization of the brain. Notably, we found that genetic inactivation or pharmacological inhibition of the ABL kinases suppressed lung and breast cancer metastasis to the brain. ABL allosteric inhibitors effectively cross the blood-brain barrier (BBB), inhibit ABL kinases and downstream targets in brain metastases, and markedly impair metastatic colonization of the brain. Further, treatment with an ABL allosteric inhibitor increased recruitment of Iba1+ macrophages/microglia to breast cancer brain metastases. Current studies are aimed at identifying the molecular mechanisms by which ABL kinase signaling regulates the crosstalk between cancer cells and macrophages/microglia, with the aim of disrupting metastatic colonization of the brain parenchyma. These data reveal, for the first time, a role for ABL kinases in promoting brain colonization by metastatic tumors, and demonstrate that ABL allosteric inhibitors efficiently penetrate the BBB and inhibit intracranial growth of breast and lung cancer metastases.