Mechanisms of acquired resistance to androgen receptor targeting drugs in castration-resistant prostate cancer

Abstract

After initial response to androgen receptor (AR) targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand-binding domain of AR may confer resistance to enzalutamide. Emergence of AR splice variants lacking the ligand-binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for AR. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of castration resistant prostate cancer.

Keywords: abiraterone; acquired drug resistance; androgen receptor; androgen receptor splice variants; enzalutamide; glucocorticoid receptor; intratumoral androgen synthesis; prostate cancer.

Figure 1

Schematic of androgen receptor and major splice variants. (A) Functional domains of full length androgen receptor protein. NTD=N-terminal transactivation domain, DBD=DNA binding domain, H=hinge region, LBD=ligand binding domain. (B) Organization of the mRNA species encoding androgen receptor and the major splice variants. Exons 1-8 or cryptic exon 3 contained in the transcript are indicated. Shaded areas represent untranslated regions. FL=full length, CE3=cryptic exon 3, V7=variant 7, v567es=variant 5, 6, 7 exons skipped. Data for AR-V7 is from ref. [36]. Data for AR3 is from ref. [35]. Data for ARv567es is from ref. [37].