Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA381050 | ENA |
REPOSITORIES: ENA
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Project description:Prostate cancer is a leading cause of cancer-related death among men globally. It often develops resistance to standard androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as enzalutamide. This resistance highlights the urgent need for novel therapeutic strategies. ADA-308 emerges as a promising candidate, demonstrating potent inhibition of both AR-sensitive adenocarcinoma as well as enzalutamide-resistant prostate cancer cell lines. Our studies reveal that ADA-308 effectively blocks AR activity, including nuclear localization, and inhibits cell proliferation in vitro. Furthermore, ADA-308 demonstrates remarkable efficacy in vivo, showcasing a robust antitumor response in enzalutamide-resistant models. These findings establish ADA-308’s role as a potent AR inhibitor that overcomes resistance to AR-targeted therapies and highlight its potential as a novel therapeutic approach in advanced prostate cancer management.
2024-07-08 | GSE267309 | GEO
Project description:BIRC6-targeting as potential therapy for advanced, enzalutamide-resistant prostate cancer
| PRJNA310694 | ENA
Project description:Prostate cancer is the second leading cause of cancer death among men in the United States. The Androgen receptor (AR) antagonist Enzalutamide is a FDA approved therapy for treatment of late stage prostate cancer patients and is currently under clinical study for early stage prostate cancer treatment. After a short positive response period, patients will develop drug resistance. In this study we used RNA-sequencing and bioinformatics analysis to identify Notch signaling pathway as a deregulated pathway in Enzalutamide-resistant cells. NOTCH2 and c-MYC positively correlated with AR expression in patients' samples mimicking cells with Enzalutamide-resistance. In Enzalutamide-resistant cells, MR49F and C4-2R, we found that cleaved-NOTCH1, HES1 and c-MYC protein expression are significantly elevated indicating an activated NOTCH1 pathway in those cells. In addition, ADAM10 and ADAM17 had a higher expression in Enzalutamide-resistant cells, suggesting a role for S2 cleavage in the increased cleaved NOTCH1 expression. Furthermore, treatment of Enzalutamide-resistant cells with PF-03084014 in combination with Enzalutamide increased cell death, decreased colony formation ability and re-sensitized Enzalutamide-resistant cells to Enzalutamide. Knockdown of NOTCH1 in C4-2R increases Enzalutamide sensitivity by decreasing cell proliferation and increasing cell death. In a 22RV1 xenograft model, PF-03084014 and Enzalutamide induced a decrease in tumor growth through a reduced cell proliferation and increased apoptosis. These results indicate that Notch1 signaling can contribute to Enzalutamide-resistance in Prostate cancer and inhibition of this pathway can re-sensitize resistant cells to Enzalutamide.
2019-04-01 | GSE123379 | GEO
Project description:Various mechanisms have been reported to be responsible for enzalutamide resistance in prostate cancer. In our previous studies, we have demonstrated that the histone acetyltransferase EP300 is highly expressed in castration therapy-resistant prostate cancer. In the present study, we investigated the role of EP300/CREBBP in enzalutamide-resistant prostate cancer. Enzalutamide resistant and control DuCaP cells generatd previously were treated with histone acetyltransferase (C646) and bromodomain (I-CBP112) inhibitors of EP300/CREBBP. Additionally Enzalutamide resistant cells under 5 µM enzalutamide treatment and control LNCaP cells were analyzed. DuCaP and LNCaP cells were seeded in 6-well-plates at 8 x 10^5 and 6 x 10^5 cells per well. The following day, DuCaP cells were treated with 8 µM enzalutamide, 10 µM C646, 10 µM I-CBP112 or DMSO equivalent for 24 hr.
2021-02-17 | GSE163240 | GEO
Project description:The standard of care for patients with advanced form of prostate cancer, castration-resistant, now includes enzalutamide, a second generation antiandrogen. However, most of the treated patients will develop resistance to enzalutamide based therapy in around a year, succumbing to lethal disease. Investigating the transcriptome of enzalutamide-resistant prostate cancer cell lines, we identified CXCR7 as one of the most upregulated genes suggesting its role in advanced prostate cancer. CXCR7, known as an atypical G-coupled receptor, is engaged in many physiological and pathological processes. Here we show that in prostate cancer CXCR7 is tightly regulated by androgen receptor (AR), which directly binds to CXCR7 gene promoter and enhancer and represses its transcription. In turn, CXCR7 in prostate cancer reduces enzalutamide toxicity and promotes cell survival and invasiveness. We identified that CXCR7 forms an integral complex with ARRB2 and activates ERK1/2, eliciting pro-survival MAPK pathway. Enzalutamide treatment combined with MAPKK specific inhibitor, trametinib, reversed enzalutamide resistance in prostate cancer in vitro and in vivo. Taken together our findings highlight the critical role of CXCR7 in enzalutamide-resistant prostate cancer and open an avenue for developing novel anti-CXCR7 therapies to improve survival in patients with advanced prostate cancer.
2019-04-06 | GSE104935 | GEO
Project description:Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a FDA-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period to enzalutamide, tumors will develop drug resistance. In this study, we uncovered that DNA methylation was deregulated in enzalutamide-resistant cells. DNMT activity and DNMT3B expression were upregulated in resistant cell lines. Enzalutamide induced the expression of DNMT3A and DNMT3B in prostate cancer cells with a potential role of p53 and pRB in this process. The overexpression of DNMT3B3, a DNMT3B variant, promoted an enzalutamide-resistant phenotype in C4-2B cell lines. Inhibition of DNA methylation and DNMT3B knockdown induced a re-sensitization to enzalutamide. Decitabine treatment in enzalutamide-resistant cells induced a decrease of the expression of AR-V7 and changes of genes for apoptosis, DNA repair and mRNA splicing. Combination treatment of Decitabine and enzalutamide induced a decrease of tumor weight, Ki-67 and AR-V7 expression and an increase of cleaved-caspase3 levels in 22Rv1 xenografts. The collective results suggest that DNA methylation pathway is deregulated after enzalutamide resistance onset and that targeting DNA methyltransferases restores the sensitivity to enzalutamide in prostate cancer cells.
2021-09-22 | GSE184168 | GEO
Project description:Prostate cancer C4-2B cells were cultured in enzalutamide in a dose-escalation manner. After sixty passages cells were resistant to enzalutamide, with a specific sets of genes been deregulated. We performed global gene expression analysis by cDNA microarrays to identify genes responsible for enzalutamide resistance in C4-2B-MDVR cells. Enzalutamide resistant C4-2B-MDVR cells were selected from C4-2B cells during long time enzalutamide treatment. Genes responsible for enzalutamide resistance were identified using C4-2B vs. C4-2B-MDVR RNA extraction and hybridization on Affymetrix microarrays.
2015-04-09 | E-GEOD-64143 | biostudies-arrayexpress
Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) â?? the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. RNA-seq profiles of prostate cancer cell lines to understand gene expression associated with enzalutamide treatment
2016-06-10 | E-GEOD-69896 | biostudies-arrayexpress
Project description:In 2012, the US Food and Drug Administration approved enzalutamide (Xtandi) for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. In most patients, enzalutamide halts progression of the disease for a short period of time, but patients usually relapse, which is associated with poor prognosis. Identifying the genes and pathways that the cancer cells use to overcome enzalutamide are of interest, because new interventions aimed at preventing relapse after enzalutamide therapy would have therapeutic value to late-stage prostate cancer patients. In this study, we took advantage of RNA interference techniques and an in vitro model of castration-resistant prostate cancer cells to identify genes that drive resistance to enzalutamide.
2021-01-10 | GSE156816 | GEO