Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer

As prostate cancer (PCa) progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor micro-environment contribute to the emergence of unique biological characteristics under the selective pressureof external stresses. These stresses include the therapies appliedinthe clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumormicro- andmacro-environment. The androgen receptor (AR) is a key gene involved in PCa etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy, antiandrogens such as enzalutamide, and androgen synthesis inhibitionwith abiraterone acetate.One such resistancemechanismis the synthesis of constitutively active AR variants lacking the canonical ligand-binding domain. This review focuses on the etiology, characterization, biological properties, and emerging data contributingto the clinical characteristicsofARvariants, andsuggests approaches to-full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.