Scaffolds, Sponges, and Steroids: Unraveling the RNA–Kinase Cross-Talk in Advanced Prostate Cancer

Prostate cancer remains a leading cause of male cancer mortality, principally due to the inevitable transition from androgen-sensitive disease to lethal castration-resistant prostate cancer (CRPC). This review synthesizes the multifaceted molecular mechanisms driving this therapeutic failure, moving beyond a catalogue of signaling nodes to a structural and kinetic analysis of resistance networks. We dissect the reactivation of Androgen Receptor (AR) signaling through the lens of key kinase cascades, specifically the PI3K/AKT/mTOR and MAPK axes, and their regulation of the steroidogenic gatekeeper CYP17A1. Special emphasis is placed on the structural determinants of CYP17A1 activity, including the critical Asn202 gating mechanism and the "backdoor" pathway of dihydrotestosterone (DHT) biosynthesis that bypasses canonical testosterone intermediates. Furthermore, we integrate the "hydrophobic spine" hypothesis of kinase activation to explain the efficacy and failure of Type I and Type II kinase inhibitors. In parallel, we unravel the regulatory complexity of non-coding RNAs (ncRNAs), detailing how upregulated transcripts like LINC00675 and Lnc-ZNF30-3 function as dynamic scaffolds and competing endogenous RNAs (ceRNAs) to stabilize AR and promote epithelial-mesenchymal transition (EMT). By converging these insights with emerging therapeutic strategies, such as next-generation lipid nanoparticle (LNP)-mediated RNA interference utilizing hexagonal HII phase endosomal escape, we provide a comprehensive roadmap for dismantling the molecular fortresses of advanced prostate cancer.