A clinically relevant androgen receptor mutation confers resistance to 2nd generation anti-androgens enzalutamide and ARN-509
Menée in vitro et in vivo, cette étude met en évidence un mécanisme de résistance à deux anti-androgènes de deuxième génération, l'enzalutamide et un composé appelé ARN-509; dans le traitement d'un cancer de la prostate résistant à la castration
Despite the impressive clinical activity of 2nd generation anti-androgens enzalutamide and ARN-509 in prostate cancer patients, acquired resistance invariably emerges. To identify the molecular mechanisms underlying acquired resistance, we developed and characterized cell lines resistant to ARN-509 and enzalutamide. In a subset of cell lines, ARN-509 and enzalutamide exhibit agonist activity, due to a missense mutation (F876L) in the ligand binding domain of the androgen receptor (AR). AR F876L is sufficient to confer resistance to ARN-509 and enzalutamide in in vitro and in vivo models of CRPC. Importantly, the AR F876L mutant is detected in plasma DNA from ARN-509 treated patients with progressive CRPC. Thus, selective outgrowth of AR F876L is a clinically relevant mechanism of 2nd generation anti-androgen resistance that can potentially be targeted with next generation anti-androgens.