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

چکیده اصلی

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.

ترجمه فارسی چکیده

متاستازهای مغزی (BrM) یک عارضه شایع و ویرانگر در سرطان پستان مثبت به HER2 (HER2+) هستند که تا ۳۰ درصد از بیماران مبتلا به بیماری متاستاتیک را درگیر می‌کنند. اگرچه تراستوزوماب درمان سرطان پستان مثبت به HER2 را تغییر داده است، اما اثربخشی آن در برابر BrM همچنان محدودیت دارد. این مطالعه بررسی کرد که آیا درمان رادیونوکلئیدی هدفمند به HER2 با استفاده از [177Lu]Lu-DOTA-trastuzumab می‌تواند مقاومت به تراستوزوماب را در متاستازهای مغزی مثبت به HER2 غلبه کند. درمان با [177Lu]Lu-DOTA-trastuzumab باعث مرگ سلولی شد و در ۴۰ درصد از حیوانات درمان شده منجر به بهبودی کامل شد. این درمان با سمیت عصبی قابل مشاهده همراه نبود. یافته‌ها نشان می‌دهد که درمان رادیونوکلئیدی هدفمند به HER2 می‌تواند مقاومت به تراستوزوماب را غلبه کند.

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