Androgen receptor (T877A mutant) (AR-T877A)

The Androgen receptor T877A mutant is a specific somatic missense mutation in the ligand-binding domain of the human androgen receptor, involving a threonine-to-alanine substitution at residue 877 [1, 5]. This mutation is highly prevalent in advanced prostate cancer, particularly in approximately 25-33% of patients with metastatic castration-resistant prostate cancer (mCRPC), and is the defining feature of the LNCaP cell line [12]. The T877A mutation induces 'ligand promiscuity,' expanding the receptor's binding pocket to allow activation by non-androgenic steroids such as progesterone, estrogen, and glucocorticoids, as well as by certain anti-androgen drugs like hydroxyflutamide [5, 12]. This functional shift allows the receptor to maintain growth-promoting transcriptional activity despite androgen deprivation therapy, driving tumor progression and drug resistance [2, 6]. Clinically, the presence of this mutation often leads to the 'anti-androgen withdrawal syndrome,' where stopping a drug like flutamide results in a paradoxical decrease in PSA levels [12, 13]. Modern therapeutic strategies focus on second-generation anti-androgens that overcome this agonist switch or novel degraders like PROTACs that eliminate the mutant protein entirely [14].

Other names

Thr877Ala androgen receptorT877A-ARLNCaP-type androgen receptor mutationAndrogen receptor T877A variant

The primary mechanism of action for drugs targeting the T877A mutant androgen receptor involves competitive antagonism of the ligand-binding domain to block transcriptional activity and downstream oncogenic signaling [14]. While first-generation anti-androgens like flutamide can paradoxically act as agonists for this mutant, second-generation agents such as enzalutamide and apalutamide are designed to maintain antagonistic activity [14]. Additionally, novel therapeutic approaches include proteolysis-targeting chimeras (PROTACs) that facilitate the targeted degradation of the mutant receptor protein via the ubiquitin-proteasome pathway [14].