Presentation Abstract

Abstract Number: 3386
Presentation Title: Mechanisms of resistance to enzalutamide in LNCaP models
Presentation Time: Tuesday, Apr 09, 2013, 8:00 AM -12:00 PM
Location: Hall A-E, Poster Section 42
Poster Board Number: 11
Author Block: Yohann Loriot, Alexander Wyatt, Nader Al Nakouzi, Eliana Beraldi, Paul Toren, Ka Mun Nip, Martin Gleave, Amina Zoubeidi. Vancouver Prostate Centre, Vancouver, BC, Canada
Abstract Body: Background
MDV3100 is a potent androgen receptor (AR) antagonist with activity in castration resistant prostate cancer (CRPC); however, progression to MDV3100-resistant (MDV-R) CRPC frequently occurs with rising serum PSA levels suggesting reactivation of AR pathway. We sought to identify AR-based mechanisms of resistance.
We treated human CRPC LNCAP-derived xenografts with MDV3100 and assessed androgen receptor (AR) levels and localization as well as genomic alterations versus controls. We also generated by selection MDV3100-R LNCaP-derived sub-lines to study mechanisms of resistance to MDV3100.
Serum and tumoral PSA levels were consistently increased in resistant xenogratfs as compared with sensitive xenografts along with AR nuclear localization. MDV3100 did not induce any new mutation in the DNA binding domain and any AR DNA gene amplification. AR full-length (ARfl ) and AR-V7 splicing variant were both highly expressed in RNA sequencing compared to CRPC LNCaP xenografts. However, it was no enrichment of AR-V7 versus ARfl in LNCaP MDV-R xenografts. Interestingly, AR was found in the nucleus and constitutively binding to DNA on androgen response element on PSA enhancer as measured by Chromatin immunoprecipitation in MDV-R cell lines compared to CRPC cell lines. These data were translated by increase of AR responsive genes at both mRNA and protein levels.
MDV-R LNCaP cells exhibited AR overexpression without any significant genomic alterations. While MDV3100 induces both ARfl and AR-V7 levels, no enrichment of AR-V7 was detected. Immunofluorescence , CHIP and qPCR studies suggest that ARfl overexpression remains a significant mechanism of resistance to MDV3100 similar to resistance from chronic androgen depletion.