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

Lookup NU author(s): Evangelia Kounatidou, Dr Sirintra Nakjang, Dr Stuart McCracken, Professor Craig RobsonORCiD, Dr Dominic Jones, Dr Luke GaughanORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

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.

Publication metadata

Author(s): Kounatidou E, Nakjang S, McCracken SRC, Dehm SM, Robson CN, Jones D, Gaughan L

Publication type: Article

Publication status: Published

Journal: Nucleic Acids Research

Year: 2019

Volume: 47

Issue: 11

Pages: 5634-5647

Print publication date: 20/06/2019

Online publication date: 22/04/2019

Acceptance date: 10/04/2019

Date deposited: 03/05/2019

ISSN (print): 0305-1048

ISSN (electronic): 1362-4962

Publisher: Oxford University Press

URL: https://doi.org/10.1093/nar/gkz286

DOI: 10.1093/nar/gkz286

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