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

Overview

1. Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX USA
2. The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX USA
3. Department of Cell Biology and Genetics, Naresh K. Vashisht College of Medicine, Texas A&M University Health Science Center, Bryan, TX USA
4. Department of Translational Medicine, Naresh K. Vashisht College of Medicine, Texas A&M University Health Science Center, Houston, TX USA
5. Institute of Biosciences & Technology, Texas A&M University Health Science Center, Houston, TX USA

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE2034, at NCBI GEO; found in the text, “RET activity is enriched in patients with BCBM…”

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 2 keywords, 14 MeSH terms, 5 funders, 33 references.

Cite

This paper

Regua, A. T., Bindal, S., Najjar, M. K., Tran, P.-L., Cha, J., Shams, S. S., & Lo, H.-W. (2026). RET receptor tyrosine kinase promotes breast cancer metastasis to the brain and RET inhibitors pralsetinib and selpercatinib suppress breast cancer brain metastases. Cell death & disease, 17(1), 679. https://doi.org/10.1038/s41419-026-08890-z

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