Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA310694 | ENA |
REPOSITORIES: ENA
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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 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:The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for new therapeutic strategies targeting key resistant drivers such as AR variants like AR-V7 and steroidogenic enzymes such as AKR1C3 to overcome drug resistance and improve outcomes for patients with advanced prostate cancer. Here we have designed, synthesized, and characterized a novel class of LX compounds targeting both the AR/AR-Variants and AKR1C3 pathways. Molecular docking and in vitro studies demonstrated that LX compounds bind to the AKR1C3 active sites and inhibit AKR1C3 enzymatic activity. LX compounds were also shown to reduce AR/AR-V7 expression and inhibit their target gene signaling. LX1 inhibited the conversion of androstenedione into testosterone in tumor-based ex vivo enzyme assays. In addition, LX1 inhibited the growth of cells resistant to antiandrogens including enzalutamide, abiraterone, apalutamide and darolutamide in vitro. A synergistic effect was observed when LX1 was combined with antiandrogens and taxanes, indicating the potential for this combination in treating resistant prostate cancer. Treatment with LX1 significantly decreased tumor volume, serum PSA levels, as well as reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 was found to overcome resistance to enzalutamide treatment, and its combination with enzalutamide further suppressed tumor growth in both the CWR22Rv1 xenograft and LuCaP35CR PDX models. Collectively, the dual effect of LX1 in reducing AR signaling and intratumoral testosterone, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer.
2024-07-18 | GSE271696 | GEO
Project description:The first line of therapy for advanced prostate cancer (PCa) is androgen-deprivation therapy (ADT) through surgical or chemical castration; however, in the majority of cases, tumors relapse in a hormone refractory or castration resistant prostate cancer (CRPC) form. Once the PCa has recurred in CRPC form, it progresses to a highly aggressive disease with frequent metastasis and poses an increased risk of morbidity and death This study shows that the loss of PP2Acα methylation in enzalutamide (Enza)-resistant CRPC cells plays a central role in imparting the resistant to the cancer cells by stabilizing the interaction of MED1, BRD4, and AR associated transcriptional complex, thereby amplifying the oncogenic AR transcriptional output through chromatin re-modulatory mechanism. Further, this study demonstrates that targeting the PP2ACα regulatory mechanisms or its downstream epigenetic effectors/mechanisms abolish the enzalutamide-resistance phenotype, thus paving the way for the development of more effective therapeutics to curtail mCRPC. The below given experiments validate the above findings.
2023-06-07 | GSE205419 | GEO
Project description:The first line of therapy for advanced prostate cancer (PCa) is androgen-deprivation therapy (ADT) through surgical or chemical castration; however, in the majority of cases, tumors relapse in a hormone refractory or castration resistant prostate cancer (CRPC) form. Once the PCa has recurred in CRPC form, it progresses to a highly aggressive disease with frequent metastasis and poses an increased risk of morbidity and death. This study shows that the loss of PP2Acα methylation in enzalutamide (Enza)-resistant CRPC cells plays a central role in imparting the resistant to the cancer cells by stabilizing the interaction of MED1, BRD4, and AR associated transcriptional complex, thereby amplifying the oncogenic AR transcriptional output through chromatin re-modulatory mechanism. Further, this study demonstrates that targeting the PP2ACα regulatory mechanisms or its downstream epigenetic effectors/mechanisms abolish the enzalutamide-resistance phenotype, thus paving the way for the development of more effective therapeutics to curtail mCRPC. The below given experiments validate the above findings.
2023-06-08 | GSE205348 | GEO
Project description:Polyamide Efficacy in Enzalutamide-Resistant Prostate Cancer
| PRJNA381050 | ENA
Project description:<p>We examined genetic resistance to second generation androgen targeting therapies (abiraterone acetate or enzalutamide) by analyzing whole exome sequencing of patient-matched pre-treatment and post-resistance tumors from a series of castrate-resistant prostate cancer (CRPC) patients. Abiraterone resistant tumors harbored alterations in AR and MYC, whereas patients treated with enzalutamide had acquired alterations in the cell cycle pathway. We experimentally confirmed expression of cell-cycle kinases sufficed to drive enzalutamide resistance, which was mitigated through CDK4/6 blockade. These observations link genetic resistance to specific therapeutic agents to inform strategies in genomically selected advanced CRPC.</p>
| phs001447 | dbGaP
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: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: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