scholarly journals ERG induces taxane resistance in castration-resistant prostate cancer

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Giuseppe Galletti ◽  
Alexandre Matov ◽  
Himisha Beltran ◽  
Jacqueline Fontugne ◽  
Juan Miguel Mosquera ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Taxane Resistance

scholarly journals MicroRNAs as potential therapeutics to enhance chemosensitivity in advanced prostate cancer

2018 ◽  
Author(s):  
Hui-Ming Lin ◽  
Iva Nikolic ◽  
Jessica Yang ◽  
Lesley Castillo ◽  
Niantao Deng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Therapeutic Potential ◽  
Castration Resistant Prostate Cancer ◽  
Compensatory Mechanisms ◽  
Castration Resistant ◽  
Genome Wide ◽  
Taxane Resistance ◽  
A Genome ◽  
Pc3 Cells ◽  
Taxane Chemotherapy

AbstractDocetaxel and cabazitaxel are taxane chemotherapy treatments for metastatic castration-resistant prostate cancer (CRPC). However, therapeutic resistance remains a major issue. MicroRNAs are short non-coding RNAs that can silence multiple genes, regulating several signalling pathways simultaneously. Therefore, synthetic microRNAs may have therapeutic potential in CRPC by regulating genes involved in taxane response and minimise compensatory mechanisms that cause taxane resistance. To identify microRNAs that can improve the efficacy of taxanes in CRPC, we performed a genome-wide screen of 1280 microRNAs in the CRPC cell lines PC3 and DU145 in combination with docetaxel or cabazitaxel treatment. Mimics of miR-217 and miR-181b-5p enhanced apoptosis significantly in PC3 cells in the presence of these taxanes. These mimics downregulated at least a thousand different transcripts, which were enriched for genes with cell proliferation and focal adhesion functions. Individual knockdown of a selection of 46 genes representing these transcripts resulted in toxic or taxane sensitisation effects, indicating that these genes may be mediating the effects of the microRNA mimics. A range of these genes are expressed in CRPC metastases, suggesting that these microRNA mimics may be functional in CRPC. With further development, these microRNA mimics may have therapeutic potential to improve taxane response in CRPC patients.

scholarly journals LncRNA HORAS5 promotes taxane resistance in castration-resistant prostate cancer via a BCL2A1-dependent mechanism

Epigenomics ◽  
2020 ◽  
Vol 12 (13) ◽  
pp. 1123-1138 ◽  
Author(s):  
Perla Pucci ◽  
Erik Venalainen ◽  
Ilaria Alborelli ◽  
Luca Quagliata ◽  
Cheryl Hawkes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Count ◽  
Clinical Samples ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Genes Expression ◽  
Taxane Resistance ◽  
Reverse Transcription Quantitative Pcr ◽  
Induced Apoptosis ◽  
Dependent Mechanism

Background: Castration-resistant prostate cancer (CRPC) is an incurable malignancy. Long noncoding RNAs (lncRNAs) play key roles in drug resistance. Materials & methods: LncRNA HORAS5 role in cabazitaxel resistance (i.e., cell-count, IC50 and caspase activity) was studied via lentiviral-mediated overexpression and siRNA-based knockdown. Genes expression was analyzed with RNA-sequencing, reverse transcription quantitative PCR (RT-qPCR) and western blot. HORAS5 expression was queried in clinical database. Results: Cabazitaxel increased HORAS5 expression that upregulated BCL2A1, thereby protecting CRPC cells from cabazitaxel-induced apoptosis. BCL2A1 knockdown decreased cell-count and increased apoptosis in CRPC cells. HORAS5-targeting antisense oligonucleotide decreased cabazitaxel IC50. In CRPC clinical samples, HORAS5 expression increased upon taxane treatment. Conclusion: HORAS5 stimulates the expression of BCL2A1 thereby decreasing apoptosis and enhancing cabazitaxel resistance in CRPC cells.

scholarly journals Circulating Cell-Free DNA as Biomarker of Taxane Resistance in Metastatic Castration-Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4055
Author(s):  
Edoardo Francini ◽  
Fang-Shu Ou ◽  
Justin Rhoades ◽  
Eric G. Wolfe ◽  
Edward P. O’Connor ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Copy Number Alterations ◽  
Castration Resistant Prostate Cancer ◽  
Primary Resistance ◽  
Cell Free Dna ◽  
Future Studies ◽  
Castration Resistant ◽  
Free Dna ◽  
Taxane Resistance ◽  
Circulating Cell Free Dna

There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana–Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.

Abstract LB-59: ERG induces taxane resistance in castration-resistant prostate cancer.

2013 ◽  
Author(s):  
Giuseppe Galletti ◽  
Himisha Beltran ◽  
Alexandre Matov ◽  
Jacqueline Fontugne ◽  
Juan Miguel Mosquera ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Taxane Resistance

Cell plasticity associated to taxane-resistance in preclinical cell models and in circulating tumor cells from metastatic castration-resistant prostate cancer patients.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 238-238
Author(s):  
Ruth Montalbo ◽  
Natalia Jiménez ◽  
Maria Mila ◽  
Òscar Reig ◽  
Iván Victoria ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cell Models ◽  
Castration Resistant Prostate Cancer ◽  
Cell Plasticity ◽  
Mesenchymal Transition ◽  
Castration Resistant ◽  
Taxane Resistance

238 Background: Treatment resistance is associated with tumor cells molecular plasticity. In metastatic castration resistant prostate cancer (mCRPC), alterations in androgen receptor (AR) have been described as predictors of shorter response to hormonal treatments. Previously, we associated epithelial to mesenchymal transition (EMT) phenotype with chemotherapy resistance. However, other molecular changes responsible of such resistance should be elucidated. Here, we investigate the effect of taxanes on cell plasticity through in vitro models and in circulating tumor cells (CTCs) from mCRPC patients. Methods: Molecular differences due to taxane-exposure were evaluated in cell models of mCRPC (PC-3 and DU-145 resistant to taxanes). Global gene expression (GE) analysis was performed using Affimetrix GeneChip Human Gene 2.0 arrays. GE related with AR axis, EMT and neuroendocrine (NE) phenotypes was validated by quantitative (qRT-PCR). Clinical validation was performed in CTCs from 24 mCRPC patients collected prior and post taxane-treatment. CTCs enrichment was achieved by Isoflux technology through a personalized combination of EpCAM, CDH2 and PSCA antibodies. Results: GE analysis revealed a different deregulation pattern related to the EMT, NE and AR-related phenotypes in resistant CRPC-cells compared to parental cells. Docetaxel resistance was more associated to an EMT phenotype while cabazitaxel resistance to NE patterns. GE patterns in CTCs at post taxane-treatment showed a common upregulation of AR-related genes compared to pre-treatment collected samples. Moreover, most patients experienced upregulation of EMT and NE markers after treatment, which was more pronounced after docetaxel than cabazitaxel therapy. Conclusions: GE changes related to taxane-resistance observed in pre-clinical models also occur in CTCs. This supports the great value of CTCs to evaluate cell plasticity due to taxanes treatment. Further investigation is ongoing to better characterize cellular plasticity and to improve personalized therapeutic strategies that would enhance better clinical outcomes in mCRPC.

The influence of treatment sequence in the prognostic value of TMPRSS2-ERG as a biomarker of taxane resistance in castration-resistant prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 235-235
Author(s):  
Òscar Reig ◽  
Mercedes Marin ◽  
Maria Mila ◽  
Albert Font ◽  
Montserrat Domenech ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Value ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Reverse Transcription Pcr ◽  
Castration Resistant ◽  
Taxane Resistance ◽  
Sequential Experiments ◽  
The Impact

235 Background: TMPRSS2-ERG expression at peripheral blood has been correlated with lower docetaxel benefit. This multicenter study prospectively assessed the role of TMPRSS2-ERG mRNA as a taxane-resistance biomarker in blood and retrospectively in tumors, and explored the impact of prior abiraterone/enzalutamide (A/E) in castration-resistant prostate cancer (CRPC) patients and in vitro. Methods: TMPRSS2-ERG was tested by quantitative reverse-transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2-ERG expression was correlated with PSA-progression-free survival (PFS), radiological-PFS (RX-PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. ERG knockdown, combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Results: In the multivariate analysis prior A/E (HR: 1.833; P = 0.005) and blood TMPRSS2-ERG (HR: 2, 95%CI; 1.1-3.67; P = 0.018) , were independently associated to lower PSA-PFS. In patients without prior A/E, both blood and tumor TMPRSS2-ERG independently predicted lower PSA-PFS (HR 2.92; P = 0.014 and HR 1.82; P = 0.045, respectively) to taxanes. This was not observed in patients with prior A/E. There was a significant interaction between blood TMPRSS2-ERG detection and prior A/E related to PSA-PFS (P = 0.032) and RX-PFS (P = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced neuroendocrine markers and reduced E-cadherin expression. Conclusions: Prior hormone-therapy may influence taxanes response and TMPRSS2-ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow-up evaluation.

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