Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation

Abstract

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment.

Enzalutamide-Resistant Progression of Castration-Resistant Prostate Cancer Is Driven via the JAK2/STAT1-Dependent Pathway

“…Another study also involved genetic analyses in three 22RV1-based models constructed by the concomitant treatment of ADT with ABI, ENZ, and their combination on 22RV1 cells. The final results in these drug-resistant cellular models confirmed that the expression of several AR target genes, such as FKBP5, PMEPA1, and TMPRSS2, significantly increased except for the general increase in the expression of AR-FL and AR-v7 (Simon et al, 2021). Our previous research screened four genes from ENZ-resistant C4-2B cells, which were CCNA2, CKAP2L, NCAPG, and NUSAP1, and confirmed that the protein levels of these four genes also remained higher in ENZ-resistant xenograft tumor tissues (Feng et al, 2021a; Feng et al, 2021b).…”

Prostate cancer resistance leads to a global deregulation of translation factors and unconventional translation

“…With the advent of potent AR-antagonists such as ENZ as first line therapy for castration-resistant prostate cancer (CRPC) patients, a few ENZ-resistant cellular models have been described ( 57 , 58 ). Among the first and most widely characterized ENZ-resistant cells were MR49F ( 31 , 59 , 60 ), generated through serial passage of LNCaP cells (androgen-sensitive prostate adenocarcinoma cells) in ENZ-treated mice.…”

Idarubicin combats abiraterone and enzalutamide resistance in prostate cells via targeting XPA protein

“…The mechanisms underlying the progression of abiraterone and enzalutamide resistance remain unclear. It is widely accepted that AR reactivation [ 29 , 30 ] and DNA repair [ 35 ] are involved in the advancement of resistance to second-generation androgen receptor antagonists. In addition, androgen deprivation regulated the DNA damage response via cross-talk between the AR pathway and DNA repair [ 18 ].…”