Glutamate Ionotropic Kainate Receptors as Therapeutic Targets in Enzalutamide-Resistant and Neuroendocrine Prostate Cancer

Through in-depth analysis of clinical cohorts, we found that glutamate ionotropic receptor kainate (GRIK) family members, specifically GRIK2 and GRIK5, are highly expressed in neural lineage plastic prostate cancer cells, NEPC patient derived xenografts, and NEPC patient samples.

Their expression positively correlates with neuroendocrine markers and inversely correlates with androgen receptor (AR) activity. Additionally, functional analyses indicated that AR has a direct transcriptional inhibitory effect on GRIK2 and GRIK5, and the absence of AR signaling leads to the upregulation of GRIK2 and GRIK5. Further RNA sequence analysis exhibited that GRIK5 silencing repro-grams the cellular transcriptome, resulting in significant downregulation of AR sig-naling and fatty acid metabolism, while simultaneously activating immune and in-flammatory responses in enzalutamide resistant prostate cancer cells.