AUTHOR=Jiménez Natalia , Reig Òscar , Montalbo Ruth , Milà-Guasch Maria , Nadal-Dieste Lluis , Castellano Giancarlo , Lozano Juan José , Victoria Iván , Font Albert , Rodriguez-Vida Alejo , Carles Joan , Suárez Cristina , Domènech Montserrat , Sala-González Núria , Fernández Pedro Luis , Rodríguez-Carunchio Leonardo , Díaz Sherley , Prat Aleix , Marín-Aguilera Mercedes , Mellado Begoña 

TITLE=Cell Plasticity-Related Phenotypes and Taxanes Resistance in Castration-Resistant Prostate Cancer

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.594023

DOI=10.3389/fonc.2020.594023

ISSN=2234-943X

ABSTRACT=<p>The prostatic tumor cells plasticity is involved in resistance to hormone-therapy, allowing these cells to survive despite androgen receptor inhibition. However, its role in taxanes resistance has not been fully established. Gene expression of plasticity-related phenotypes such as epithelial-mesenchymal transition (EMT), stem cell-like and neuroendocrine (NE) phenotypes was studied <italic>in vitro</italic>, <italic>in silico</italic>, in circulating tumor cells (CTCs) (<italic>N</italic>=22) and in tumor samples (<italic>N</italic>=117) from taxanes-treated metastatic castration-resistant prostate cancer (mCRPC) patients. Docetaxel (D)-resistant cells presented a more pronounced EMT phenotype than cabazitaxel (CZ)-resistant cells. <italic>In silico</italic> analysis revealed <italic>ESRP1</italic> down-regulation in taxane-exposed mCRPC samples. Cell plasticity-related changes occurred in CTCs after taxanes treatment. Tumor EMT phenotype was associated with lower PSA progression-free survival (PFS) to D (<italic>P</italic>&lt;0.001), and better to CZ (<italic>P</italic>=0.002). High <italic>ESRP1</italic> expression was independently associated with longer PSA-PFS (<italic>P</italic>&lt;0.001) and radiologic-PFS (<italic>P</italic>=0.001) in D and shorter PSA-PFS in the CZ cohort (<italic>P</italic>=0.041). High <italic>SYP</italic> expression was independently associated with lower PSA-PFS in D (<italic>P</italic>=0.003) and overall survival (OS) in CZ (<italic>P</italic>=0.002), and high <italic>EZH2</italic> expression was associated with adverse OS in D-treated patients (<italic>P</italic>=0.013). In conclusion, EMT profile in primary tumor is differentially associated with D or CZ benefit and NE dedifferentiation correlates with adverse taxanes clinical outcome.</p>