RET receptor tyrosine kinase promotes breast cancer metastasis to the brain and RET inhibitors pralsetinib and selpercatinib suppress breast cancer brain metastases.

Patients with breast cancer brain metastases (BCBM) exhibit dismal prognosis, largely due to the insufficient biological understanding and the scarcity of therapeutics that can penetrate the blood-brain barrier (BBB). This study was focused on Rearranged during transfection (RET) receptor tyrosine kinase that has been implicated in non-small cell lung cancer (NSCLC) and thyroid cancer. Here, we report that RET activation is elevated in patient BCBM samples compared to matched primary tumors (N = 30), and in three brain-tropic breast cancer cell lines compared to the parental lines. High RET pathway activation is associated with worse brain metastasis-free survival in patients with HER2-enriched and triple-negative breast cancer (TNBC). Using TNBC cells with ectopic RET overexpression, we demonstrated that RET strongly promoted their preferential metastasis to the brain in mice with intracardiac injections of tumor cells. Using intracranial tumor implantation of the isogenic lines, we found that RET significantly enhanced the formation and progression of brain tumors in vivo. Moreover, we observed that selective BBB-permeable RET inhibition using Pralsetinib and Selpercatinib, FDA-approved for NSCLC and thyroids cancer, significantly reduced cell viability, enhanced apoptosis, and attenuated migration of brain-tropic breast cancer cells in vitro. Using two mouse studies modeling multi-organ metastases and breast tumor formation in the brain, we observed that RET inhibition significantly prevented the circulating tumor cells from forming brain metastases and suppressed the growth of intracranially implanted tumor cells. Together, our findings demonstrated that RET functions as a novel mediator of BCBM and that RET inhibitors showed promising efficacy for BCBM.