¹⁷⁷Lu-trastuzumab radionuclide therapy: a promising strategy for trastuzumab-resistant brain metastases in HER2+ breast cancer.

Authors

Liliana Santos, Ivanna Hrynchak, José Sereno, Hugo R S Ferreira, Magda Silva, Alexandra Fonseca, Rui Almeida, Paulo Teixeira, Antero J Abrunhosa, Célia M F Gomes

Published in

Molecular biomedicine. Volume 7. Issue 1. Sep 14, 2026. Epub Sep 14, 2026.

Abstract

Brain metastases (BrM) are a frequent and devastating complication of HER2-positive (HER2+) breast cancer (BC), affecting up to 30% of patients with metastatic disease. Although trastuzumab has transformed HER2+ BC treatment, its efficacy against BrM remains limited by brain-specific resistance mechanisms and heterogeneous blood-brain barrier (BBB) permeability. Here, we investigated whether HER2-targeted radionuclide therapy (TRT) using the β-emitting radioimmunoconjugate [¹⁷⁷Lu]Lu-DOTA-trastuzumab could overcome trastuzumab resistance in HER2+ brain metastatic lesions. Brain-tropic cells retained HER2 expression but showed reduced sensitivity to trastuzumab, indicating the emergence of resistance mechanisms independent of target loss. By contrast, treatment with [¹⁷⁷Lu]Lu-DOTA-trastuzumab produced robust DNA double-strand break-mediated cytotoxicity irrespective of trastuzumab sensitivity, demonstrating that resistance to antibody-mediated signaling inhibition does not confer cross-resistance to radiation-induced cell killing. In vivo, a single dose of [¹⁷⁷Lu]Lu-DOTA-trastuzumab markedly reduced tumor progression and led to complete remission of established BrM in 40% of treated animals, whereas unconjugated trastuzumab showed minimal therapeutic benefit. Importantly, treatment was not associated with detectable neurotoxicity. While dynamic contrast-enhanced MRI demonstrated widespread BBB disruption across metastatic lesions, [⁸⁹Zr]Zr-DFO-trastuzumab PET revealed marked heterogeneity in intracranial antibody delivery, with tracer uptake restricted to a subset of lesions. Collectively, these findings demonstrate that HER2-TRT can overcome trastuzumab resistance and eradicate brain metastatic lesions. Moreover, immuno-PET provides a non-invasive biomarker of intracranial antibody accessibility, supporting a theranostic strategy that combines patient stratification with TRT for HER2+ BrM.

PMID:
42734882
Bibliographic data and abstract were imported from PubMed on 15 Sep 2026.

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