Saracatinib synergizes with enzalutamide to downregulate androgen receptor activity in castration resistant prostate cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA956116 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24182884_1.fastq.gz | Fastqsanger.gz | |||
| SRR24182884_2.fastq.gz | Fastqsanger.gz | |||
| SRR24182885_1.fastq.gz | Fastqsanger.gz | |||
| SRR24182885_2.fastq.gz | Fastqsanger.gz | |||
| SRR24182886_1.fastq.gz | Fastqsanger.gz |
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Project description:Prostate cancer (PCa) remains the most diagnosed non-skin cancer amongst the American male population. Treatment for localized prostate cancer consists of androgen deprivation therapies (ADTs), which typically inhibit androgen production and the androgen receptor (AR). Though initially effective, a subset of patients will develop resistance to ADTs and the tumors will transition to castration-resistant prostate cancer (CRPC). Second generation hormonal therapies such as abiraterone acetate and enzalutamide are typically given to men with CRPC. However, these treatments are not curative and typically prolong survival only by a few months. Several resistance mechanisms contribute to this lack of efficacy such as the emergence of AR mutations, AR amplification, lineage plasticity, AR splice variants (AR-Vs) and increased kinase signaling. Having identified SRC kinase as a key tyrosine kinase enriched in CRPC patient tumors from our previous work, we evaluated whether inhibition of SRC kinase synergizes with enzalutamide or chemotherapy in several prostate cancer cell lines expressing variable AR isoforms. We observed robust synergy between the SRC kinase inhibitor, saracatinib, and enzalutamide, in the AR-FL+/AR-V+ CRPC cell lines, LNCaP95 and 22Rv1. We also observed that saracatinib significantly decreases AR Y534 phosphorylation, a key SRC kinase substrate residue, on AR-FL and AR-Vs, along with the AR regulome, supporting key mechanisms of synergy with enzalutamide. Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs.
| S-EPMC10348659 | biostudies-literature
Project description:We performed RNA-seq to evaluate the consequence of saracatinib's effects on androgen receptor residue Y534 as it pertains to Androgen Receptor gene signatures
2023-04-20 | GSE229805 | GEO
Project description:The goal of this study was to determine how androgen receptor inhibition alters transcriptional programs in prostate cancer cells. LNCaP prostate cancer cells were grown in 10% charcoal-stripped serum (CSS) supplemented with 0.5 nanomolar dihydrotestosterone (DHT), in CSS without DHT modeling castration, with CSS + DHT but in the presence of 10 micromolar enzalutamide, or in CSS without DHT (castrated) and in the presence of enzalutamide for 72 hours. Analysis shows that androgen receptor target genes are reduced with castration, enzalutamide or the combination of castration + enzalutamide.
2022-05-12 | GSE202755 | GEO
Project description:Molecular mechanisms underlying resistance to androgen deprivation therapy (ADT) and, in particular, to antiandrogen Enzalutamide, in treating castration-resistant prostate cancer (CRPC), remain incompletely understood. Through screening >120 CRPC patient samples, we observed 3 expression patterns of androgen receptor (AR) protein: primarily nuclear (nuc-AR), mixed nuclear/cytoplasmic expression (nuc/cyto-AR), and low/no expression (AR-/lo). Xenograft CRPC modeling in 4 models (i.e., LNCaP, VCaP, LAPC4, and LAPC9) recapitulated the 3 AR expression patterns in castration-resistant tumors developed from parental androgen-dependent tumors. Strikingly, although the 3 CRPC models that retained AR expression (LNCaP, VCaP, and LAPC4) responded, to different levels and in different kinetics, to Enzalutamide, the AR-/lo LAPC9 CRPC was completely refractory to Enzalutamide. By combining whole-genome RNA-Seq and biochemical analyses together with experimental combinatorial therapy in the LNCaP and LAPC9 models, we identified BCL-2 as a critical therapeutic target in both AR+/hi and AR-/lo, Enzalutamide-resistant CRPC models.
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Project description:Effect of castration, bicalutamide, and enzalutamide on androgen receptor binding in Hi-Myc mouse prostate tumors
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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
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Project description:Enzalutamide (formerly MDV3100 and available commercially as Xtandi), a novel androgen receptor (AR) signaling inhibitor, blocks the growth of castration-resistant prostate cancer (CRPC) in cellular model systems and was shown in a clinical study to increase survival in patients with metastatic CRPC. Enzalutamide inhibits multiple steps of AR signaling: (1) binding of androgens to AR, (2) AR nuclear translocation, and (3) association of AR with DNA. Here we used Affymetrix human genome microarray technology to investigate the global programme of gene expression of LNCaP cells in response to enzalutamide alone and in the context of DHT-stimulated androgen receptor gene expression. LNCaP cells were grown in RPMI 1640 supplemented with 5% hormone depleted FBS and treated with vehicle (control sample) , DHT (100 nM), enzalutamide (1 or 10 M-BM-5M) or DHT (100 nM) plus enzalutamide (1 or 10 M-BM-5M)for 16 hours for RNA extraction and hybridization. Each condition was done in triplicate.
2013-04-01 | E-GEOD-44905 | 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
Project description:Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is therefore urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the non-receptor tyrosine kinase Src, observing promising antitumor effects of its small molecule inhibitor Saracatinib in BTC preclinical models. The presence of an active Src protein was investigated by immunohistochemistry in 19 surgical samples from BTC patients. Upon Saracatinib treatment, the phosphorylation of Src and of its downstream transducers was evaluated in the BTC cell lines TFK-1, EGI-1, HuH28 and TGBC1-TKB. The effect of Saracatinib on proliferation and migration was analyzed in these same cell lines, and its antitumor activity was essayed in EGI-1 mouse xenografts. Saracatinib-modulated transcriptome was profiled in EGI-1 cells and in tumor samples of the xenograft model. Src was activated in about 80% of the human BTC samples. In cultured BTC cell lines, low-dose Saracatinib counteracted the activation of Src and of its downstream effectors, increased the fraction of cells in G0/G1 phase, and inhibited cell migration. At high concentrations (median dose from 2.26 to 6.99 µM), Saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, Saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. We here provide a demonstration that the targeted inhibition of Src kinase by Saracatinib is of therapeutic benefit in preclinical models of BTC. We propose our results as a basis for the design of Saracatinib-based clinical applications. EGI-1 cell line treated with Saracatinib at the dose of 10 µM vs EGI-1 cell line untreated; EGI-1 xenograft treated with Saracatinib at the dose of 25 mg/Kg/die vs EGI-1 xenograft untreated Transcriptional alteration mediated by Saracatinib in vitro and in vivo
2012-08-02 | E-GEOD-36622 | biostudies-arrayexpress
Project description:To investigate the mechanisms of drug resistance and castration resistance in prostate cancer, we performed proteomic sequencing on androgen-dependent prostate cancer cells (LNCaP) and androgen-independent cells (AI) treated with enzalutamide.
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