Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients
Posted on 2016-01-26 - 05:00
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 patientsâ serum, and the functional characterization of these mutants in order to provide personalized recommendations regarding the best future therapy.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Lallous, Nada; Volik, Stanislav; Awrey, Shannon; Leblanc, Eric; Tse, Ronnie; Murillo, Josef; et al. (2016). Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.3596834.v1
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
AUTHORS (15)
NL
Nada Lallous
SV
Stanislav Volik
SA
Shannon Awrey
EL
Eric Leblanc
RT
Ronnie Tse
JM
Josef Murillo
KS
Kriti Singh
AA
Arun Azad
AW
Alexander Wyatt
SL
Stephane LeBihan
KC
Kim Chi
MG
Martin Gleave
PR
Paul Rennie
CC
Colin Collins
AC
Artem Cherkasov