Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA310694 | ENA |
REPOSITORIES: ENA
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Project description:This experiment investigates the transcriptional landscape of LNCaP prostate cancer cells in response to hormonal and epigenetic therapy under hypoxic conditions using single-cell RNA sequencing (scRNA-seq). The study aims to model drug resistance mechanisms by exposing cells to chronic hypoxia and treating them with Enzalutamide, an androgen receptor inhibitor, with and without Tazemetostat, an EZH2 inhibitor. Cells were sampled across multiple time points to identify resistant clones and assess how combination therapy alters gene expression. This experiment provides insight into the gene expression signatures associated with resistance and explores potential biomarkers relevant to advanced prostate cancer progression.
2025-08-07 | E-MTAB-16057 | biostudies-arrayexpress
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:Enzalutamide, a second-generation androgen receptor (AR) antagonist, has represented the association with improved overall survival in men with prostate cancer (PCa). However, PCa patients receiving enzalutamide will eventually develop resistance through various mechanisms without effective regimens. Here, we observed a higher level of formin-like 2 (FMNL2) in enzalutamide-resistant PCa cells. Functionally, FMNL2 knockdown partially re-sensitized enzalutamide-resistant PCa cells. Mechanistically, FMNL2 directly interacted with SRC kinase through FMNL2-FH1 and SRC-SH3 domain, which induced AR translocation from the cytoplasm to the nucleus, resulting in increased expression of the AR-targeted genes and leading to resistance to enzalutamide. Consistently, SRC inhibitor dasatinib rescued enzalutamide sensitivity and inhibited the proliferation of enzalutamide-resistant cancer cells. Taken together, our findings demonstrate a substantial role for FMNL2/SRC interaction in the regulation of AR translocation, suggesting that targeting FMNL2-mediated SRC activation might be a potential therapeutic strategy for enzalutamide-resistant PCa, and dasatinib could be an option.
2025-01-13 | PXD059539 | Pride
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:Polyamide Efficacy in Enzalutamide-Resistant Prostate Cancer
| PRJNA381050 | ENA
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: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:<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:INTRODUCTION: CDK4-selective inhibitors are emerging as promising anti-cancer agents. Relative to dual CDK4/6 inhibitors, CDK4-selective inhibitors have potential to retain efficacy while improving tolerability. However, the therapeutic value and mechanistic consequences of selectively targeting CDK4 in prostate cancer remain undefined. Here, we investigated the therapeutic potential of CDK4 inhibitors AU2-94 and atirmociclib across diverse prostate cancer models. METHODS: Anti-proliferative activity was assessed in a panel of prostate cancer cell lines spanning AR-driven hormone-sensitive and AR-independent castration-resistant states, including therapy-resistant models. Efficacy was further evaluated in organoids from patient-derived xenografts and xenograft mouse models. Biochemical and molecular analyses were performed to define CDK4 selectivity, RB pathway engagement, transcriptional consequences, and downstream effects on cell cycle and resistance-associated programs. AU2-94 was also tested in combination with standard-of-care therapies (enzalutamide, docetaxel) and the PI3K inhibitor alpelisib. RESULTS: AU2-94 exhibited greater selectivity for CDK4 compared to atirmociclib. AU2-94 supressed proliferation across prostate cancer models irrespective of AR status and retained activity in aggressive and therapy-resistant settings. In RB-proficient models, AU2-94 reduced RB phosphorylation, attenuated E2F1-dependent transcriptional outputs, activated AR signalling, and decreased expression of proliferation-associated factors such as c-Myc and FOXM1. In vivo, AU2-94 significantly inhibited tumour growth in both AR-driven (LNCaP) and AR-independent (PC3) xenografts and suppressed RB pathway signalling in tumour tissue. Moreover, AU2-94 enhanced anti-tumour responses in combination with enzalutamide, docetaxel, or alpelisib, demonstrating additive or synergistic effects associated with reinforced cell-cycle blockade and suppression of resistance-associated signalling. CONCLUSION: These findings establish selective CDK4 inhibition as a therapeutically active and mechanistically rational strategy in prostate cancer, and support AU2-94 as a candidate for further preclinical and clinical development, including in combination regimens for advanced and therapy-resistant disease.
2026-05-28 | GSE330358 | GEO