Abstract Breast cancer is the most common cancer among American women, with over 315,000 new cases and more than 42,000 deaths projected in 2025. Triple-negative breast cancer (TNBC), the most aggressive subtype, has a high incidence of brain metastasis (BrainMet)—up to 45%. Clinical studies show that TNBC patients with BrainMet have the shortest survival times (4-6 months) compared to those with lung, liver, or bone metastases. This poor prognosis is mainly due to a lack of actionable therapeutic targets and blood-brain barrier (BBB)-permeable drugs. No effective TNBC-BrainMet therapeutics have been identified, underscoring the urgent need for novel treatment modalities. Rearranged during transfection (RET) is implicated in tumorigenesis and metastatic progression in non-small cell lung cancers, thyroid carcinoma, and breast cancers. The orally FDA-approved RET inhibitors, Pralsetinib and Selpercatinib, demonstrated brain penetration, with 70-91% intracranial response rates in lung cancer patients with BrainMet, suggesting their possible utility in treating TNBC-BrainMet. In this study, we investigated the role of RET in TNBC-BrainMet and assessed the therapeutic efficacy of these selective RET inhibitors as a TNBC-BrainMet treatment. Our datamining analyses revealed that RET is hyperactivated in TNBC-BrainMet patients and is associated with worsened survival outcomes. Overexpression of RET in TNBC cells promoted brain metastasis in our intracardiac injection and intracranial inoculation mouse models. Treatment with RET inhibitors reduced tumor burden and brain metastasis in the BrainMet prevention mouse study in vivo. However, we observed drug resistance to RET inhibitors in the BrainMet treatment model in vivo. We also found lower sensitivity to RET inhibitors in brain-tropic TNBC cells compared to parental TNBC cells. To identify the potential mechanisms of resistance, we further investigated whether RET pathway is co-activated with other oncogenic pathways in breast cancer brain metastasis using the TCGA database analyses. We observed that RET is concurrently activated with multiple signaling pathways, including t-GAS, VEGF, AKT, and ERK. Notably, co-inhibition of RET and these signaling pathways produced synergistic effects in suppressing the proliferation of brain-tropic TNBC cells. Our findings suggested that these co-inhibitions may overcome RET monotherapy resistance in TNBC-BrainMet. In summary, targeting RET is promising for preventive therapy; co-inhibition of RET and its associated pathways may overcome RET monotherapy resistance and advance TNBC-BrainMet treatment, providing preclinical evidence to support future clinical evaluation and development of new effective therapies for TNBC patient with brain metastasis. Citation Format: Phi-Long Tran, Elissa Bloom, Angelina Regua, Shivani Bindal, Mariana Najja, Sham Syed, Hui-Wen Lo. Understanding and overcoming resistance of triple-negative breast cancer brain metastases to RET monotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7112.
Tran et al. (Fri,) studied this question.