Abstract
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.
Highlights
Cell plasticity refers to the ability of cancer cells to switch their phenotype in response to environmental conditions, facilitating therapy fail
We investigated gene expression changes in tumors from metastatic castrationresistant prostate cancer (mCRPC) patients treated with taxanes, by using RNA-seq data from the study of Abida et al [35] Within AR signaling inhibitors (ARSI)-naïve patients, ESRP1 expression was significantly lower in taxane-exposed respect to taxane-naïve patients (P=0.007) (Figure 3B)
In this study we show that changes in cell plasticity-related phenotypes occur after taxane exposure in in vitro models of CRPC, in CRPC biopsies analyzed in silico, and in circulating tumor cells (CTCs) from patients with mCRPC treated with taxanes
Summary
Cell plasticity refers to the ability of cancer cells to switch their phenotype in response to environmental conditions, facilitating therapy fail. In prostate cancer (PC) cell plasticity allows cancer cells to reprogram and survive despite androgen receptor (AR) inhibition, being considered one of the mechanisms involved in androgen deprivation therapy (ADT) resistance [1]. Throughout this process, tumor cells may develop epithelialmesenchymal transition (EMT), and/or evolve towards an stem cell-like (SCL) or neuroendocrine (NE) phenotypes, and it is possible that they acquire mixed or intermediate phenotypes [2, 3]. Different degrees of NE dedifferentiation (from pure, mixed or intermediate adenocarcinoma/NE phenotypes) have been observed in biopsies from mCRPC patients who progressed to abiraterone and its presence is associated with an adverse clinical outcome [11]. No specific clinical strategies are defined based on the presence of these phenotypes and no targeted therapies have demonstrated benefit in mCRPC patients
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