Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation
MetadataShow full item record
AuthorSimon, Iris; Perales Romero, Sonia; Casado Medina, Laura; Rodríguez Martínez, Alba; Garrido Navas, María del Carmen; Puche Sanz, Ignacio; Díaz Mochón, Juan José; Lorente Acosta, José Antonio; Lupiañez, Pablo; Serrano, María José; Real, Pedro J.
Castration resistant prostate cancerAndrogen receptorAR-V7AR-V9Transcriptional regulationNovel hormonal agentsAbirateroneEnzalutamideCross-resistance
Simon, I.; Perales, S.; Casado-Medina, L.; Rodríguez-Martínez, A.; Garrido-Navas, M.d.C.; Puche-Sanz, I.; Diaz-Mochon, J.J.; Alaminos, C.; Lupiañez, P.; Lorente, J.A.; et al. Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation. Cancers 2021, 13, 1483. https://doi.org/ 10.3390/cancers13061483
SponsorshipInstituto de Salud Carlos III PI17/00989; European Regional Development Fund "A way to build Europe"; Ramon y Cajal - Ministry of Economy and Competitiveness RYC-2015-18382; Ministry of Education, Culture and Sport FPU14/05461; University of Granada
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.