2. Academic Validation
  3. Drivers of AR indifferent anti-androgen resistance in prostate cancer cells

Drivers of AR indifferent anti-androgen resistance in prostate cancer cells

  • Sci Rep. 2019 Sep 24;9(1):13786. doi: 10.1038/s41598-019-50220-1.
Florian Handle 1,  Stefan Prekovic 1 2,  Christine Helsen 1,  Thomas Van den Broeck 1 3,  Elien Smeets 1,  Lisa Moris 1 3,  Roy Eerlings 1,  Sarah El Kharraz 1,  Alfonso Urbanucci 4,  Ian G Mills 5 6 7,  Steven Joniau 3,  Gerhardt Attard 8,  Frank Claessens 9
Affiliations

Affiliations

  • 1 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
  • 2 Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 3 Department of Urology, University Hospitals Leuven, Leuven, Belgium.
  • 4 Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
  • 5 Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, Forskningsparken, University of Oslo, Oslo, Norway.
  • 6 Centre for Cancer Research and Cell Biology, Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Queen's University, Belfast, UK.
  • 7 Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  • 8 UCL Cancer Institute, University College London, 72 Huntley Street, London, UK.
  • 9 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. frank.claessens@kuleuven.be.
PMID: 31551480 DOI: 10.1038/s41598-019-50220-1
Abstract

Inhibition of the Androgen Receptor (AR) by second-generation anti-androgens is a standard treatment for metastatic castration resistant prostate Cancer (mCRPC), but it inevitably leads to the development of resistance. Since the introduction of highly efficient AR signalling inhibitors, approximately 20% of mCRPC patients develop disease with AR independent resistance mechanisms. In this study, we generated two anti-androgen and castration resistant prostate Cancer cell models that do not rely on AR activity for growth despite robust AR expression (AR indifferent). They are thus resistant against all modern AR signalling inhibitors. Both cell lines display cross-resistance against the chemotherapeutic drug docetaxel due to MCL1 upregulation but remain sensitive to the PARP Inhibitor olaparib and the pan-BCL inhibitor obatoclax. RNA-seq analysis of the anti-androgen resistant cell lines identified hyper-activation of the E2F cell-cycle master regulator as driver of AR indifferent growth, which was caused by deregulation of cyclin D/E, E2F1, RB1, and increased Myc activity. Importantly, mCRPC tissue samples with low AR activity displayed the same alterations and increased E2F activity. In conclusion, we describe two cellular models that faithfully mimic the acquisition of a treatment induced AR independent phenotype that is cross-resistant against chemotherapy and driven by E2F hyper-activation.

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