Project description:Castration resistant prostate cancer (CRPC) develops resistance to antiandrogens affecting Androgen Receptor (AR) signaling through a variety of mechanism. Because of this, the efficacy of androgen receptor targeted therapy remains limited for many patients with CRPC. We developed C42B-Abiraterone (Abi) and resistance cells to study changes in transcriptomic profile compared to parental cells.
Project description:Super Enhancers (SEs) play a key role in castration-resistant prostate cancer (CRPC) drug resistance. By integrating ChIP-seq and RNA-seq analyses, we identified aberrantly activated super enhancers at the ELF3 and JUNB loci driving their transcriptional up-regulation in abiraterone-resistant prostate cancer cells. Mechanistically, ELF3/JUNB complex directly interacted and activated WNT11 to promote drug resistance and neuroendocrine transformation of prostate cancer cells. In vitro and in vivo experiments confirmed that targeting ELF3/JUNB significantly restored abiraterone sensitivity. This study reveals a critical role of the SE-driven ELF3/JUNB-WNT11 axis in CRPC resistance, providing a new potential therapeutic target to overcome abiraterone resistance.
Project description:Super Enhancers (SEs) play a key role in castration-resistant prostate cancer (CRPC) drug resistance. By integrating ChIP-seq and RNA-seq analyses, we identified aberrantly activated super enhancers at the ELF3 and JUNB loci driving their transcriptional up-regulation in abiraterone-resistant prostate cancer cells. Mechanistically, ELF3/JUNB complex directly interacted and activated WNT11 to promote drug resistance and neuroendocrine transformation of prostate cancer cells. In vitro and in vivo experiments confirmed that targeting ELF3/JUNB significantly restored abiraterone sensitivity. This study reveals a critical role of the SE-driven ELF3/JUNB-WNT11 axis in CRPC resistance, providing a new potential therapeutic target to overcome abiraterone resistance.
Project description:To identify the molecular signature associated with abiraterone acetate (AA) response and mechanisms underlying AA resistance in castration-resistant prostate cancer patient-derived xenografts (PDXs).
Project description:Here, we analyze gene expression of prostate cancer cell line VCaP (VCaP WT) and VCaP after long time treatment with abiraterone (VCaP AA) in order to investigate possible resistance mechanisms to second-generation antiandrogens.
Project description:Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20-40% of the patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance. Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients. Results: Thirty cytosines showed significant modification differences (FDR q < 0.05) between the AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, the AA-sensitive patients, but not AA-resistant patients, lost interindividual variation of cfDNA modification shortly after starting AA-treatment, but such variation returned to initial levels in the later phases of treatment. Conclusions: Our findings provide a list of potential biomarkers for prediction of AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients.
Project description:We report RNA sequencing data on serial biopsies of prostate cancer VCaP xenografts as the tumors pass from androgen-sensitivity (Pre-Cx), to castration resistance (CRPC, castration resistant prostate cancer), onto resistance to dual therapy with abiraterone plus enzalutamide (AER). From comparison of these RNAseq data sets, we were able to determine differentially expressed genes between the AER/CRPC and Pre-Cx states that could mediate resistance to androgen deprivation therapies.