Advanced prostate cancers disproportionally affect veteran populations in the US. One key feature of the advanced diseases is the development of anti-androgen receptor therapy resistance through a mechanism of tumor lineage plasticity, which contributes to the lethal progression of prostate cancer. However, the mechanisms underlying the aberration are poorly understood, which severely hinders the development of effectively therapeutic intervention of the advanced diseases. Our preliminary studies found that a novel reprogramming of adrenergic receptor signaling occurs in progression to lethal forms of prostate cancer, where beta-blocker drug target gene is silenced and, in contrast, adrenergic ligand synthesis genes, and a different member of the adrenergic receptor family and its signaling pathway genes are induced. In line with the change, beta-blocker displayed no significant effect on the treatment-induced neuroendocrine prostate cancer (t-NEPC) tumors. Remarkably, small molecule antagonists of the other adrenergic receptor developed by us and others displayed high potency in growth inhibition of several enzalutamide-resistant /t-NEPC cell and PDX tumor models. Our further analyses showed that the aberrant signaling stimulates programs for cancer stem-like cell (CSC), EMT and NEPC features, with alterations of local chromatin histone marks. Moreover, our data suggest that a chemokine receptor appears to interact with the adrenergic receptor and facilitate the signaling. Therefore, we will take genetics, pharmacological, functional genomics and epigenomics approaches to test the hypotheses that reprogramming of adrenergic receptor signaling drives tumor plasticity and therapy resistance through cross-talks and that targeting the aberrant signaling axis is efficacious and safe for treatment of therapy-resistant, lethal forms of PCa.