BIRC6-targeting as potential therapy for advanced, enzalutamide-resistant prostate cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE77516 | GEO | 2016/02/04
SECONDARY ACCESSION(S): PRJNA310694
REPOSITORIES: GEO
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Project description:Enzalutamide (ENZ) is a potent androgen receptor (AR) antagonist with activity in castration-resistant prostate cancer (CRPC); however, progression to ENZ-resistant (ENZ-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full length (ARFL) or variants (AR-Vs) in disease progression. To define functional roles of ARFL and AR-Vs in ENZ-R CRPC, we designed 3 antisense oligonucleotides (ASO) targeting exon 1, intron 1, and exon 8 in AR pre-mRNA to knockdown either ARFL alone, or ARFL plus AR-Vs, and examined their respective effects in LNCaP-derived ENZ-R, as well as M12 and 22Rv1, cells. ENZ-R LNCaP xenografts express high levels of both ARFL and AR-V7 compared to CRPC LNCaP xenografts. In particular, ARFL levels were ~20-fold higher than AR-V7. ENZ-R LNCaP sub-lines, derived by selection from the ENZ xenografts, also expressed uniformly high levels of ARFL and AR-V7 compared to CRPC LNCaP cells. In addition, both ARFL and AR-V7 are highly expressed in the nuclear fractions of ENZ-R-LNCaP. In ENZ-R LNCaP cells, knockdown of ARFL alone, or ARFL plus AR-Vs, similarly induced apoptosis, suppressed cell growth and AR-regulated gene expression in vitro, and delayed tumour growth in vivo. In 22Rv1 cells that are inherently resistant to ENZ, knockdown of both ARFL and AR-Vs more potently suppressed cell growth, AR transcriptional activity and AR-regulated gene expression than knockdown of ARFL alone. These data indicate the AR is an important driver of ENZ resistance, and while the contributions of ARFL and AR-Vs can vary across cell systems, ARFL is the key driver in the ENZ-R LNCaP model. AR targeting strategies against both ARFL and AR-Vs is a rational approach for AR-dependent CRPC. CRPC and ENZ-R LNCaP xenografts were generated as described in: Gleave, M.E., et al., Serum prostate specific antigen levels in mice bearing human prostate LNCaP tumors are determined by tumor volume and endocrine and growth factors. Cancer Res, 1992. 52(6): p. 1598-605.
2015-01-01 | GSE55345 | GEO
Project description:Acquisition of resistance to the next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castrate-resistant prostate cancer (CRPC). Most ENZ-resistant (ENZ-R) CRPCs are androgen receptor (AR)-positive (CRPCAR+), but often negative for prostate-specific antigen (PSA), a well-established surrogate of AR activity, implying the emergence of AR-indifferent disease. Through genome-wide ChIP-seq and RNA-seq profiling in disease-relevant ENZ-R CRPCAR+ cells, we identified a unique set of gained AR binding sites (ARBS-G) lacking the canonical DNA binding elements of AR and the pioneer factor FOXA1. ARBS-G loci are highly enriched with CpG islands and significantly overlapped with the binding sites of the unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. Expression of CXXC5 and its downstream targets including inhibitor of differentiation-1 (ID1) was upregulated in ENZ-R CRPCAR+ cell lines, patient-derived xenografts (PDXs) and patient specimens. Genetic depletion of AR, CXXC5 or ID1 restored ENZ sensitivity in human ENZ-R CRPCAR+ cells. Most importantly, ENZ-R CRPCAR+ cells, organoids, xenografts and PDXs were invariably hypersensitive to the novel BET-CBP/p300 dual inhibitor NEO2734. These results reveal that ENZ-R CRPCAR+ cancers are only indifferent to the canonical AR (cAR) activity, but remain addictive to the noncanonical AR (ncAR) function which is selectively vulnerable upon dual inhibition of CBP/p300 and BET family proteins.
2020-08-20 | GSE136129 | GEO
Project description:Acquisition of resistance to the next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castrate-resistant prostate cancer (CRPC). Most ENZ-resistant (ENZ-R) CRPCs are androgen receptor (AR)-positive (CRPCAR+), but often negative for prostate-specific antigen (PSA), a well-established surrogate of AR activity, implying the emergence of AR-indifferent disease. Through genome-wide ChIP-seq and RNA-seq profiling in disease-relevant ENZ-R CRPCAR+ cells, we identified a unique set of gained AR binding sites (ARBS-G) lacking the canonical DNA binding elements of AR and the pioneer factor FOXA1. ARBS-G loci are highly enriched with CpG islands and significantly overlapped with the binding sites of the unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. Expression of CXXC5 and its downstream targets including inhibitor of differentiation-1 (ID1) was upregulated in ENZ-R CRPCAR+ cell lines, patient-derived xenografts (PDXs) and patient specimens. Genetic depletion of AR, CXXC5 or ID1 restored ENZ sensitivity in human ENZ-R CRPCAR+ cells. Most importantly, ENZ-R CRPCAR+ cells, organoids, xenografts and PDXs were invariably hypersensitive to the novel BET-CBP/p300 dual inhibitor NEO2734. These results reveal that ENZ-R CRPCAR+ cancers are only indifferent to the canonical AR (cAR) activity, but remain addictive to the noncanonical AR (ncAR) function which is selectively vulnerable upon dual inhibition of CBP/p300 and BET family proteins.
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Project description:Androgen-deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen-deprived conditions. Unlike most pre-existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate-specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence-based chemical screening. We identified flavopiridol, a broad spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81). Importantly, this broad spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient-derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad spectrum CDK inhibitors, might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide.
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Project description:HIPSTR is a conserved lncRNA that is transcribed antisense to TFAP2A gene. Unlike previously reported antisense lncRNAs, HIPSTR expression does not correlate with the expression of its antisense counterpart. HIPSTR depletion in HEK293 and H1BP cells predominantly affects genes involved in early organismal development and cell differentiation. H1BP cells were transfected with antisense oligonucleotides (ASOs) targeting HIPSTR (ASO #0, ASO #1 or ASO #2) or control scrambled ASO (ASO CTL); transfections with each targeting ASO were done in duplicate, transfections with control ASO were done in triplicate.
2016-09-08 | E-GEOD-77936 | biostudies-arrayexpress
Project description:End-stage breast cancers are clonally heterogeneous and harbor many poorly-understood treatment resistance mechanisms. We therefore established multiple Patient-Derived-Xenograft (PDX) models to study genomic events driving advanced disease. Comparative whole-genome sequencing of paired primary tumors and their PDX models demonstrated that PDX retain the vast majority of the structural variations and copy number aberrations seen within the originating tumor, and with high fidelity. Variant allele fractions (VAF) were preserved, even for rare mutations. Clonal representation is therefore a transplantable phenotype, indicating that genomic heterogeneity can be regulated in a tumor-autonomous mechanism, indifferent to host immune status. Mutations and gene rearrangements were documented in the ESR1 gene in three of five sequenced luminal PDX/progenitor tumor pairs (amplification, point mutation and translocation), and were associated with clinical endocrine response phenotypes, differential PDX estradiol responsiveness and all induced estradiol-independent growth in standard cell lines. PDX models are therefore a significant new tool for fundamental studies on the molecular basis for resistance to endocrine treatment in advanced breast cancer. reference x sample
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Project description:HIPSTR is a conserved lncRNA that is transcribed antisense to TFAP2A gene. Unlike previously reported antisense lncRNAs, HIPSTR expression does not correlate with the expression of its antisense counterpart. HIPSTR depletion in HEK293 and H1BP cells predominantly affects genes involved in early organismal development and cell differentiation. HEK293 cells were transfected with antisense oligonucleotides (ASOs) targeting HIPSTR (ASO #1 or ASO #2) or control scrambled ASO (ASO CTL); transfection with each ASO was done in triplicate.
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