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By integrating high-dimensional imaging analysis at single-cell resolution, in-depth mechanistic dissection, extensive therapeutic studies in defined preclinical models, and CTC-based correlative studies associated with a Phase Ib clinical trial, this investigation highlights therapy-induced cellular diversification, exposes the 3 BCL-2-upreulated CRPC subtypes with varying AR expression and signaling intensity (i.e., AR + BCL-2 + , AR -/lo BCL-2 + , and AR cyto BCL-2 + ), advances our mechanistic understanding of AR-mediated repression and ARPI-triggered activation of BCL-2 transcription, and, critically, validates BCL-2 as a therapeutic target across distinct CRPC subtypes

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The peptide was assigned three drug designations: PL-10, PLD-116, and PL14736

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