2026/04/07 by Bangwei Fang, Xiaomeng Li, Ying Lu +13 · 1 voice
Medicine · #HER2/EGFR in Cancer Research #Prostate Cancer Treatment and Research #Radiopharmaceutical Chemistry and Applications
paper · pdf · doi:10.1172/jci201090
openalex publication_date 2026/04/07 · openalex created_date 2026/04/08 · openalex updated_date 2026/07/16
Metastatic castration-resistant prostate cancer (mCRPC) remains lethal with limited treatment options. Antibody-drug conjugates (ADCs) have emerged as a transformative class across multiple solid tumors, yet their clinical application in prostate cancer has been limited. Izalontamab brengitecan (Iza-bren; BL-B01D1) is a bispecific ADC-targeting EGFR and HER3 that has demonstrated activity in other malignancies. Here, we evaluated its therapeutic potential in the treatment of prostate cancer. Multi-omics analyses revealed frequent EGFR and HER3 expression in CRPC adenocarcinoma but not in neuroendocrine subtypes. BL-B01D1 exerted potent, target-dependent cytotoxicity in prostate cancer cell lines, xenografts, and patient-derived organoids (PDOs). We highlight a representative patient with mCRPC with high EGFR/HER3 expression whose disease rapidly and durably mounted a clinical and radiologic response to BL-B01D1, concordant with matched PDO sensitivity. Mechanistic studies identified ABCG2 upregulation as a driver of acquired resistance, with genetic or pharmacologic inhibition restoring BL-B01D1 sensitivity. Importantly, tumor tissue obtained at progression after BL-B01D1 treatment confirmed ABCG2 upregulation, validating a clinically relevant resistance mechanism. These findings support BL-B01D1 as a promising therapeutic strategy in mCRPC and indicate ABCG2 may be a rational target for overcoming resistance.