Abstract:
:Resistance to androgen receptor (AR)-targeted therapies in prostate cancer (PC) is a major clinical problem. A key mechanism of treatment resistance in advanced PC is the generation of alternatively spliced forms of the AR termed AR variants (AR-Vs) that are refractory to targeted agents and drive tumour progression. Our understanding of how AR-Vs function is limited due to difficulties in distinguishing their discriminate activities from full-length AR (FL-AR). Here we report the development of a novel CRISPR-derived cell line which is a derivative of CWR22Rv1 cells, called CWR22Rv1-AR-EK, that has lost expression of FL-AR, but retains all endogenous AR-Vs. From this, we show that AR-Vs act unhindered by loss of FL-AR to drive cell growth and expression of androgenic genes. Global transcriptomics demonstrate that AR-Vs drive expression of a cohort of DNA damage response genes and depletion of AR-Vs sensitises cells to ionising radiation. Moreover, we demonstrate that AR-Vs interact with PARP1 and PARP2 and are dependent upon their catalytic function for transcriptional activation. Importantly, PARP blockade compromises expression of AR-V-target genes and reduces growth of CRPC cell lines suggesting a synthetic lethality relationship between AR-Vs and PARP, advocating the use of PARP inhibitors in AR-V positive PC.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Kounatidou E,Nakjang S,McCracken SRC,Dehm SM,Robson CN,Jones D,Gaughan Ldoi
10.1093/nar/gkz286subject
Has Abstractpub_date
2019-06-20 00:00:00pages
5634-5647issue
11eissn
0305-1048issn
1362-4962pii
5475935journal_volume
47pub_type
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journal_title:Nucleic acids research
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pub_type: 杂志文章,多中心研究
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journal_title:Nucleic acids research
pub_type: 杂志文章
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journal_title:Nucleic acids research
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journal_title:Nucleic acids research
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journal_title:Nucleic acids research
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journal_title:Nucleic acids research
pub_type: 杂志文章
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journal_title:Nucleic acids research
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pub_type: 杂志文章
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