Simon, IrisPerales, SoniaCasado-Medina, LauraRodríguez-Martínez, AlbaGarrido-Navas, Maria del CarmenPuche-Sanz, IgnacioDiaz-Mochon, Juan J.Alaminos, ClaraLupiañez, PabloLorente, Jose A.Serrano, María J.Real, Pedro J.2022-09-292022-09-292021-03-23Simon I, Perales S, Casado-Medina L, Rodríguez-Martínez A, Garrido-Navas MDC, Puche-Sanz I, et al. Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation. Cancers. 2021 Mar 23;13(6):1483http://hdl.handle.net/10668/4185Androgen 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.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Castration resistant prostate cancerAndrogen receptorAR-V7AR-V9Transcriptional regulationNovel hormonal agentsAbirateroneEnzalutamideCross-resistanceNeoplasias de la próstata resistentes a la castraciónAndrógenosElementos reguladores de la transcripciónAcetato de abirateronaMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Receptors, Cytoplasmic and Nuclear::Receptors, Steroid::Receptors, AndrogenMedical Subject Headings::Diseases::Male Urogenital Diseases::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-ResistantMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormone Antagonists::Androgen AntagonistsMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::AndrogensMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::RNA Processing, Post-Transcriptional::RNA Splicing::Alternative SplicingMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytophotometry::Flow CytometryMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Motivation::GoalsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Protein IsoformsMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell ProliferationMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Urogenital Surgical Procedures::CastrationMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell LineMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotyperesearch article33807106open access10.3390/cancers130614832072-6694PMC8004828