AR-V7 splice variant

Overview

• Why a splice variant defeats a drug, in one sentence. Alternative splicing of the androgen receptor transcript produces truncated receptors, of which AR-V7 is the commonest and best studied, that retain the DNA-binding domain but lack the ligand-binding domain; they are constitutively active, and enzalutamide and abiraterone both act on the ligand-binding domain that is no longer there. AR-V9 and AR-V567es are other described variants, less well characterised clinically.
• The original figures, with their cohort. In 62 men with metastatic castration-resistant prostate cancer starting enzalutamide or abiraterone, AR-V7 messenger RNA was detectable in circulating tumour cells in 39 percent of 31 enzalutamide-treated and 19 percent of 31 abiraterone-treated men. Prostate-specific antigen response was 0 percent in AR-V7-positive men against 53 percent (enzalutamide) and 68 percent (abiraterone) in AR-V7-negative men; median prostate-specific antigen progression-free survival on enzalutamide was 1.4 against 6.0 months and overall survival 5.5 months against not reached.
• Why the test is available and little used. A negative result does not predict response, only the absence of this one resistance mechanism, and most non-responders are AR-V7-negative. Messenger RNA and protein-based assays do not identify the same men and the test is not standardised between laboratories. And the treatments a positive result would send a man to, taxanes and radioligand therapy, tend to be given in that sequence anyway.