Frontiers in Oncology (Nov 2020)

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

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

DOI
https://doi.org/10.3389/fonc.2020.594023
Journal volume & issue
Vol. 10

Abstract

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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 in vitro, in silico, in circulating tumor cells (CTCs) (N=22) and in tumor samples (N=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. In silico analysis revealed ESRP1 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 (P<0.001), and better to CZ (P=0.002). High ESRP1 expression was independently associated with longer PSA-PFS (P<0.001) and radiologic-PFS (P=0.001) in D and shorter PSA-PFS in the CZ cohort (P=0.041). High SYP expression was independently associated with lower PSA-PFS in D (P=0.003) and overall survival (OS) in CZ (P=0.002), and high EZH2 expression was associated with adverse OS in D-treated patients (P=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.

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