Mutant androgen receptor (AR (mutant))

The mutant androgen receptor (AR) is a modified form of the wild-type AR protein, primarily characterized by point mutations in the ligand-binding domain that arise during the progression of prostate cancer [UniProt: P10275]. These mutations, such as T878A, L702H, and F877L, are a hallmark of castration-resistant prostate cancer (CRPC) and serve as a major mechanism of resistance to standard androgen deprivation therapies [PubMed: 30635434]. By altering the receptor's structure, these mutations allow it to be activated by non-androgen ligands like progesterone or glucocorticoids, or even by anti-androgen drugs intended to inhibit it [PubMed: 31558487]. Consequently, the mutant AR continues to function as a transcription factor, driving the expression of genes that promote tumor cell survival and proliferation despite low systemic testosterone levels. Therapeutic development has shifted toward next-generation inhibitors and proteolysis-targeting chimeras (PROTACs) like Bavdegalutamide that can either bind to mutated pockets or degrade the receptor entirely to bypass these resistance mechanisms [Arvinas, 2023]. Monitoring these mutations through liquid biopsies and circulating tumor DNA has become an essential strategy for personalizing treatment in advanced prostate cancer patients.

Other names

Mutated androgen receptorAR mutationsmARAndrogen receptor ligand-binding domain mutants

Drugs targeting the mutant androgen receptor primarily act through competitive antagonism of the ligand-binding domain, inhibition of nuclear translocation, or through targeted protein degradation using PROTAC technology to eliminate the receptor entirely [PubMed: 31558487, Arvinas 2023].