HOXD11-NMDAR signaling drives neuroendocrine prostate cancer and enables therapeutic intervention with memantine
Prostate cancer frequently develops resistance to androgen deprivation therapy (ADT), with adenocarcinoma-neuroendocrine prostate cancer (NEPC) lineage transformation representing a critical driver of therapeutic failure. The transgenic adenocarcinoma of mouse prostate (TRAMP) mouse model recapitulates this progression, displaying luminal adenocarcinoma at early stages and NEPC at late stages. Through single-cell transcriptomic analysis across TRAMP tumor progression, we identified Hoxd11 as a key transcriptional driver of luminal-NEPC differentiation, with its expression and regulatory activity markedly upregulated during early NEPC transformation. Genetic suppression of Hoxd11 significantly inhibited both baseline neuroendocrine differentiation and ADT-induced lineage plasticity. Mechanistically, HOXD11 directly activates FOXA2 and the N-methyl-D-aspartate receptor (NMDAR) signaling pathway (via GRIN1/GRIN3A), which is hyperactivated in NEPC and correlates with poor prognosis. Pharmacological NMDAR inhibition using the clinically approved antagonist memantine in murine models can hinder the development of NEPC. Critically, memantine also demonstrated significant efficacy in human, suppressing NEPC progression and achieving marked therapeutic responses in our clinical trial (NCT07164794), as evidenced by substantial reduction in sizes of both primary and metastatic lesions. These findings establish the HOXD11-NMDAR axis as a promising therapeutic target and provide clinical evidence supporting memantine repurposing as a viable near-term treatment strategy for NEPC.