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

Florian Handle, Stefan Prekovic, Christine Helsen, Thomas Van den Broeck, Elien Smeets, Lisa Moris, Roy Eerlings, Sarah El Kharraz, Alfonso Urbanucci, Ian G Mills, Steven Joniau, Gerhardt Attard, Frank Claessens

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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.

Original languageEnglish
Article number13786
Number of pages11
JournalScientific Reports
Volume9
DOIs
Publication statusPublished - 24 Sep 2019

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Androgen Receptors
Androgens
Prostatic Neoplasms
Castration
docetaxel
Cyclin D
Cell Line
Cyclin E
Growth
Cell Cycle
Up-Regulation
RNA
Phenotype
Drug Therapy

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Handle, F., Prekovic, S., Helsen, C., Van den Broeck, T., Smeets, E., Moris, L., ... Claessens, F. (2019). Drivers of AR indifferent anti-androgen resistance in prostate cancer cells. Scientific Reports, 9, [13786]. https://doi.org/10.1038/s41598-019-50220-1
Handle, Florian ; Prekovic, Stefan ; Helsen, Christine ; Van den Broeck, Thomas ; Smeets, Elien ; Moris, Lisa ; Eerlings, Roy ; Kharraz, Sarah El ; Urbanucci, Alfonso ; Mills, Ian G ; Joniau, Steven ; Attard, Gerhardt ; Claessens, Frank. / Drivers of AR indifferent anti-androgen resistance in prostate cancer cells. In: Scientific Reports. 2019 ; Vol. 9.
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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.",
author = "Florian Handle and Stefan Prekovic and Christine Helsen and {Van den Broeck}, Thomas and Elien Smeets and Lisa Moris and Roy Eerlings and Kharraz, {Sarah El} and Alfonso Urbanucci and Mills, {Ian G} and Steven Joniau and Gerhardt Attard and Frank Claessens",
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Handle, F, Prekovic, S, Helsen, C, Van den Broeck, T, Smeets, E, Moris, L, Eerlings, R, Kharraz, SE, Urbanucci, A, Mills, IG, Joniau, S, Attard, G & Claessens, F 2019, 'Drivers of AR indifferent anti-androgen resistance in prostate cancer cells', Scientific Reports, vol. 9, 13786. https://doi.org/10.1038/s41598-019-50220-1

Drivers of AR indifferent anti-androgen resistance in prostate cancer cells. / Handle, Florian; Prekovic, Stefan; Helsen, Christine; Van den Broeck, Thomas; Smeets, Elien; Moris, Lisa; Eerlings, Roy; Kharraz, Sarah El; Urbanucci, Alfonso; Mills, Ian G; Joniau, Steven; Attard, Gerhardt; Claessens, Frank.

In: Scientific Reports, Vol. 9, 13786, 24.09.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Drivers of AR indifferent anti-androgen resistance in prostate cancer cells

AU - Handle, Florian

AU - Prekovic, Stefan

AU - Helsen, Christine

AU - Van den Broeck, Thomas

AU - Smeets, Elien

AU - Moris, Lisa

AU - Eerlings, Roy

AU - Kharraz, Sarah El

AU - Urbanucci, Alfonso

AU - Mills, Ian G

AU - Joniau, Steven

AU - Attard, Gerhardt

AU - Claessens, Frank

PY - 2019/9/24

Y1 - 2019/9/24

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-019-50220-1

DO - 10.1038/s41598-019-50220-1

M3 - Article

C2 - 31551480

VL - 9

JO - Nature Scientific Reports

JF - Nature Scientific Reports

SN - 2045-2322

M1 - 13786

ER -

Handle F, Prekovic S, Helsen C, Van den Broeck T, Smeets E, Moris L et al. Drivers of AR indifferent anti-androgen resistance in prostate cancer cells. Scientific Reports. 2019 Sep 24;9. 13786. https://doi.org/10.1038/s41598-019-50220-1