Mechanisms of Enzalutamide Resistance in Castration-Resistant Prostate Cancer and Therapeutic Strategies to Overcome It

Abstract

Prostate cancer (PCa) is the second most common malignancy in men, and androgen deprivation therapy (ADT) is the first-line therapy. However, most cases will eventually develop into castration-resistant prostate cancer (CRPC) after ADT treatment. Enzalutamide (Enz) is a second-generation androgen receptor inhibitor approved by the Food and Drug Administration to treat patients with CRPC. Unfortunately, patients receiving Enz treatment will ultimately develop resistance via various complicated mechanisms. In this review, we introduce the emerging information on resistance mechanisms, including androgen receptorrelated signalling pathways, glucocorticoid receptor-related pathways, and metabolic mechanisms. Notably, lineage plasticity and phenotype switching, gene polymorphisms, and the relationship between microRNAs and drug resistance are addressed. Furthermore, potential therapeutic strategies for Enz-resistant CRPC treatment are suggested, which can help in the discovery of more effective and specific regimens to overcome Enz resistance.

The circRAB3IP Mediated by eIF4A3 and LEF1 Contributes to Enzalutamide Resistance in Prostate Cancer by Targeting miR-133a-3p/miR-133b/SGK1 Pathway

“…There is an urgent need to determine the mechanisms of intrinsic and acquired resistance and could result in approaches to overcome such resistance. Previous studies have revealed some major mechanisms of acquired Enz resistance, including AR mutations and splice variants of AR, intratumoral androgen biosynthesis in PCa cells, lineage plasticity of PCa, cytokine dysregulation and the specific microenvironment of PCa (30)(31)(32). However, the accurate mechanisms of the resistance to Enz are still not clear.…”