Simon, IrisPerales, SoniaCasado-Medina, LauraRodríguez-Martínez, AlbaGarrido-Navas, Maria Del CarmenPuche-Sanz, IgnacioDiaz-Mochon, Juan JAlaminos, ClaraLupiañez, PabloLorente, Jose ASerrano, María JReal, Pedro J2025-01-072025-01-072021-03-232072-6694https://hdl.handle.net/10668/28438Androgen 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/AR-V7AR-V9Novel hormonal agentsabirateroneandrogen receptorcastration resistant prostate cancercross-resistanceenzalutamidetranscriptional regulationresearch article33807106open access10.3390/cancers13061483PMC8004828https://www.mdpi.com/2072-6694/13/6/1483/pdf?version=1616558380https://pmc.ncbi.nlm.nih.gov/articles/PMC8004828/pdf