HOXD11-NMDAR signaling drives neuroendocrine prostate cancer and enables potential therapeutic intervention as a target of memantine.

Prostate cancer resistance to androgen deprivation therapy often involves neuroendocrine transformation. Using single-cell RNA sequencing of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice across pathological stages (early adenocarcinoma to late neuroendocrine prostate cancer [NEPC]), we find an early neuroendocrine-initiating cluster marked by elevated HOXD11, conserved in human NEPC. Genetic suppression of HOXD11 blocks neuroendocrine differentiation and restores androgen receptor (AR) signaling. Mechanistically, HOXD11 directly activates FOXA2 and N-methyl-D-aspartate receptor (NMDAR) subunits (GRIN1/GRIN3A), pathways upregulated in NEPC and linked to poor prognosis. Pharmacological NMDAR inhibition with memantine suppresses NEPC progression preclinically. Notably, a preliminary clinical observation in one evaluable patient with chemotherapy-failed NEPC shows radiographic regression of primary and metastatic lesions after memantine treatment. These findings establish HOXD11 as a driver of neuroendocrine transformation and support further investigation of memantine as a candidate therapeutic strategy for NEPC.