Abstract Breast cancer brain metastasis (BCBM) constitutes 10-30% of metastatic breast cancer. Clinical studies reported that BCBM patients typically have shorter survival times (6-12 months), compared to patients with lung, liver, or bone metastasis. This poor prognosis is largely attributed to the lack of actionable therapeutic targets and brain-penetrant compounds. Rearranged during transfection (RET) receptor tyrosine kinase has been implicated in tumorigenesis and metastatic progression of many solid tumor types including non-small cell lung cancer, thyroid carcinomas, and breast cancer. The FDA-approved selective RET inhibitors, pralsetinib and selpercatinib, previously show potential for brain penetration and objective intracranial response in treating brain metastases in lung cancer patients, suggesting their potential use in BCBM. In this study, we report for the first time a role for rearranged during transfection (RET) receptor tyrosine kinase in BCBM and its implications in disease progression. Furthermore, we identify a novel approach to treat BCBM using FDA-approved RET inhibitors, pralsetinib and selpercatinib. We show that RET is hyper-activated in BCBM patients and is associated with a shorter brain metastasis-free survival. We also demonstrate that overexpression of RET in parental breast cancer cells promotes brain metastasis and tumor growth in vivo. Importantly, our data showed that treatment with RET inhibitors reduces cell viability, hinders migration, and enhances apoptosis of BCBM cells in vitro. A treatment mouse model also indicated that administration of RET inhibitors significantly reduces brain metastasis and reduces tumor burden in vivo. Overall, our findings suggest a novel therapeutic strategy to treat BCBM by targeting RET and provide preclinical evidence to support future clinical evaluations.
Regua et al. (Fri,) studied this question.