Targeting GRP78 and the Proteostasis Network to Break the Therapeutic Ceiling in Neuroendocrine Prostate Cancer

ABSTRACT HSPA5 (also known as GRP78/BiP) is a master regulator of the endoplasmic reticulum (ER) stress response and a key node in the proteostasis network. In neuroendocrine prostate cancer (NEPC), an aggressive, therapy‐refractory lineage that emerges under pressure from androgen receptor (AR) directed therapies, GRP78 is upregulated and co‐opted to maintain malignant cell survival. Beyond its canonical chaperone activity, GRP78 orchestrates adaptive unfolded protein response (UPR) signaling, buffers secretory stress, and stabilizes oncogenic proteomes. These functions collectively allow NEPC cells to evade apoptosis, tolerate proteotoxic stress, and resist next generation therapeutics. This review explores the emerging role of GRP78 as a therapeutic vulnerability in NEPC. We integrate evidence from proteostasis biology, lineage plasticity, and tumor microenvironment remodeling, and highlight experimental and clinical strategies targeting GRP78 directly (e.g., chaperone inhibitors, antibody therapy, peptide displacement) or indirectly through the proteostasis machinery (e.g., ERAD modulators, proteasome inhibitors, and UPR reprogramming). By reframing NEPC not only as a lineage plastic tumor but also as a proteostasis‐addicted state, we propose that GRP78 centered intervention is a promising route to break the current therapeutic ceiling.