Upregulation of PlexinD1 activates the ErbB3/cMet-ERK/AKT-noncanonical Hedgehog/Gli1 signaling to promote aggressiveness, invasiveness, and therapy resistance of metastatic castration-resistant prostate cancer cells, which can be blocked by the PlexinD1-targeted protein inhibitor D1SP. This evidence concerns the gene GLI1 and Familial prostate cancer.