Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients

Nada Lallous, Stanislav V Volik, Shannon Awrey, Eric Leblanc, Ronnie Tse, Josef Murillo, Kriti Singh, Arun A. Azad, Alexander W. Wyatt, Stephane LeBihan, Kim N Chi, Martin E Gleave, Paul S. Rennie, Colin C. Collins, Artem Cherkasov

Research output: Contribution to journalArticleResearchpeer-review

Abstract

BACKGROUND: The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, target the androgen binding site of the receptor, competing with endogenous androgenic steroids. Several AR mutations in this binding site have been associated with poor prognosis and resistance to conventional prostate cancer drugs. In order to develop an effective CRPC therapy, it is crucial to understand the effects of these mutations on the functionality of the AR and its ability to interact with endogenous steroids and conventional AR inhibitors. RESULTS: We previously utilized circulating cell-free DNA (cfDNA) sequencing technology to examine the AR gene for the presence of mutations in CRPC patients. By modifying our sequencing and data analysis approaches, we identify four additional single AR mutations and five mutation combinations associated with CRPC. Importantly, we conduct experimental functionalization of all the AR mutations identified by the current and previous cfDNA sequencing to reveal novel gain-of-function scenarios. Finally, we evaluate the effect of a novel class of AR inhibitors targeting the binding function 3 (BF3) site on the activity of CRPC-associated AR mutants. CONCLUSIONS: This work demonstrates the feasibility of a prognostic and/or diagnostic platform combining the direct identification of AR mutants from patients serum, and the functional characterization of these mutants in order to provide personalized recommendations regarding the best future therapy.
Original languageEnglish
Article number10
Number of pages15
JournalGenome Biology
Volume17
DOIs
Publication statusPublished - 26 Jan 2016
Externally publishedYes

Keywords

  • Androgen receptor
  • Castration-resistant prostate cancer
  • Cell-free circulating DNA
  • Mutations
  • Drug resistance
  • Anti-androgens and steroids

Cite this

Lallous, Nada ; Volik, Stanislav V ; Awrey, Shannon ; Leblanc, Eric ; Tse, Ronnie ; Murillo, Josef ; Singh, Kriti ; Azad, Arun A. ; Wyatt, Alexander W. ; LeBihan, Stephane ; Chi, Kim N ; Gleave, Martin E ; Rennie, Paul S. ; Collins, Colin C. ; Cherkasov, Artem. / Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. In: Genome Biology. 2016 ; Vol. 17.
@article{739235fc929b474789ff573653753b49,
title = "Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients",
abstract = "BACKGROUND: The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, target the androgen binding site of the receptor, competing with endogenous androgenic steroids. Several AR mutations in this binding site have been associated with poor prognosis and resistance to conventional prostate cancer drugs. In order to develop an effective CRPC therapy, it is crucial to understand the effects of these mutations on the functionality of the AR and its ability to interact with endogenous steroids and conventional AR inhibitors. RESULTS: We previously utilized circulating cell-free DNA (cfDNA) sequencing technology to examine the AR gene for the presence of mutations in CRPC patients. By modifying our sequencing and data analysis approaches, we identify four additional single AR mutations and five mutation combinations associated with CRPC. Importantly, we conduct experimental functionalization of all the AR mutations identified by the current and previous cfDNA sequencing to reveal novel gain-of-function scenarios. Finally, we evaluate the effect of a novel class of AR inhibitors targeting the binding function 3 (BF3) site on the activity of CRPC-associated AR mutants. CONCLUSIONS: This work demonstrates the feasibility of a prognostic and/or diagnostic platform combining the direct identification of AR mutants from patients serum, and the functional characterization of these mutants in order to provide personalized recommendations regarding the best future therapy.",
keywords = "Androgen receptor, Castration-resistant prostate cancer, Cell-free circulating DNA, Mutations, Drug resistance, Anti-androgens and steroids",
author = "Nada Lallous and Volik, {Stanislav V} and Shannon Awrey and Eric Leblanc and Ronnie Tse and Josef Murillo and Kriti Singh and Azad, {Arun A.} and Wyatt, {Alexander W.} and Stephane LeBihan and Chi, {Kim N} and Gleave, {Martin E} and Rennie, {Paul S.} and Collins, {Colin C.} and Artem Cherkasov",
year = "2016",
month = "1",
day = "26",
doi = "10.1186/s13059-015-0864-1",
language = "English",
volume = "17",
journal = "Genome Biology",
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Lallous, N, Volik, SV, Awrey, S, Leblanc, E, Tse, R, Murillo, J, Singh, K, Azad, AA, Wyatt, AW, LeBihan, S, Chi, KN, Gleave, ME, Rennie, PS, Collins, CC & Cherkasov, A 2016, 'Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients' Genome Biology, vol. 17, 10. https://doi.org/10.1186/s13059-015-0864-1

Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. / Lallous, Nada; Volik, Stanislav V; Awrey, Shannon; Leblanc, Eric; Tse, Ronnie; Murillo, Josef; Singh, Kriti; Azad, Arun A.; Wyatt, Alexander W.; LeBihan, Stephane; Chi, Kim N; Gleave, Martin E; Rennie, Paul S.; Collins, Colin C.; Cherkasov, Artem.

In: Genome Biology, Vol. 17, 10, 26.01.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients

AU - Lallous, Nada

AU - Volik, Stanislav V

AU - Awrey, Shannon

AU - Leblanc, Eric

AU - Tse, Ronnie

AU - Murillo, Josef

AU - Singh, Kriti

AU - Azad, Arun A.

AU - Wyatt, Alexander W.

AU - LeBihan, Stephane

AU - Chi, Kim N

AU - Gleave, Martin E

AU - Rennie, Paul S.

AU - Collins, Colin C.

AU - Cherkasov, Artem

PY - 2016/1/26

Y1 - 2016/1/26

N2 - BACKGROUND: The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, target the androgen binding site of the receptor, competing with endogenous androgenic steroids. Several AR mutations in this binding site have been associated with poor prognosis and resistance to conventional prostate cancer drugs. In order to develop an effective CRPC therapy, it is crucial to understand the effects of these mutations on the functionality of the AR and its ability to interact with endogenous steroids and conventional AR inhibitors. RESULTS: We previously utilized circulating cell-free DNA (cfDNA) sequencing technology to examine the AR gene for the presence of mutations in CRPC patients. By modifying our sequencing and data analysis approaches, we identify four additional single AR mutations and five mutation combinations associated with CRPC. Importantly, we conduct experimental functionalization of all the AR mutations identified by the current and previous cfDNA sequencing to reveal novel gain-of-function scenarios. Finally, we evaluate the effect of a novel class of AR inhibitors targeting the binding function 3 (BF3) site on the activity of CRPC-associated AR mutants. CONCLUSIONS: This work demonstrates the feasibility of a prognostic and/or diagnostic platform combining the direct identification of AR mutants from patients serum, and the functional characterization of these mutants in order to provide personalized recommendations regarding the best future therapy.

AB - BACKGROUND: The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, target the androgen binding site of the receptor, competing with endogenous androgenic steroids. Several AR mutations in this binding site have been associated with poor prognosis and resistance to conventional prostate cancer drugs. In order to develop an effective CRPC therapy, it is crucial to understand the effects of these mutations on the functionality of the AR and its ability to interact with endogenous steroids and conventional AR inhibitors. RESULTS: We previously utilized circulating cell-free DNA (cfDNA) sequencing technology to examine the AR gene for the presence of mutations in CRPC patients. By modifying our sequencing and data analysis approaches, we identify four additional single AR mutations and five mutation combinations associated with CRPC. Importantly, we conduct experimental functionalization of all the AR mutations identified by the current and previous cfDNA sequencing to reveal novel gain-of-function scenarios. Finally, we evaluate the effect of a novel class of AR inhibitors targeting the binding function 3 (BF3) site on the activity of CRPC-associated AR mutants. CONCLUSIONS: This work demonstrates the feasibility of a prognostic and/or diagnostic platform combining the direct identification of AR mutants from patients serum, and the functional characterization of these mutants in order to provide personalized recommendations regarding the best future therapy.

KW - Androgen receptor

KW - Castration-resistant prostate cancer

KW - Cell-free circulating DNA

KW - Mutations

KW - Drug resistance

KW - Anti-androgens and steroids

U2 - 10.1186/s13059-015-0864-1

DO - 10.1186/s13059-015-0864-1

M3 - Article

VL - 17

JO - Genome Biology

JF - Genome Biology

SN - 1474-760X

M1 - 10

ER -