A novel CRISPR-engineered prostate cancer cell line defines the AR-V transcriptome and identifies PARP inhibitor sensitivities

Evangelia Kounatidou, Sirintra Nakjang, Stuart R.C. McCracken, Scott M. Dehm, Craig N. Robson, Dominic Jones, Luke Gaughan

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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 ARVs 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.

Original languageEnglish (US)
Pages (from-to)5634-5647
Number of pages14
JournalNucleic acids research
Volume47
Issue number11
DOIs
StatePublished - Jun 20 2019

Bibliographical note

Funding Information:
Prostate Cancer UK through a Studentship [S14-007]; Medical Research Council (MRC) [MR/P009972/1]; Cancer Research UK. Funding for open access charge: MRC. Conflict of interest statement. None declared.

Publisher Copyright:
© The Author(s) 2019.

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