Abstract LB-420: Intratumoral de novo steroid synthesis mediates prostate cancer resistance to androgen deprivation and CYP17a1 inhibition

Abstract

Abstract Prostate cancer (PCa) that relapses after androgen deprivation therapy (ADT, medical or surgical castration), termed castration resistant prostate cancer (CRPC), has increased expression of enzymes that convert adrenal dehydroepiandrosterone (DHEA) and androstenedione to testosterone and dihydrotestosterone (DHT). DHEA and androstenedione are synthesized at high levels by the adrenals through the sequential actions of CYP11A1 and CYP17A1; hence CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, mechanisms contributing to CYP17A1 inhibitor relapse remain to be determined. We show that castration resistant VCaP PCa xenografts synthesize androgens de novo at levels that fully restore androgen receptor (AR) activity and respond to abiratrone, and that development of abiraterone resistance is associated with markedly increased intratumoral CYP17A1 expression. Consistent with these results, we find that tumor expression of CYP17A1 is markedly increased in patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a T877A mutant AR are not CYP17A1 dependent, and that AR activity in these cells is instead mediated by upstream CYP11A1 dependent pregnenolone/progesterone synthesis. These findings indicate that CYP17A1 inhibitor resistant tumors are still steroid dependent and may respond to dose escalation, alternative CYP17A1 inhibitors, or agents blocking other steps in steroid synthesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-420. doi:10.1158/1538-7445.AM2011-LB-420