Abstract
BackgroundThe 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.ResultsWe 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0864-1) contains supplementary material, which is available to authorized users.
Highlights
The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form
We showed that mutations in the AR androgen binding site (ABS) contributed to treatment resistance in a subset of patients and presented the possibility of detecting these mutations in cell-free DNA (cfDNA) at the point of progression [25]
We hypothesized that the AR binding function 3 (BF3) inhibitor should not be activated by any of the mutations, because they mainly cluster in the AR ABS, a region spatially distant from the BF3 site, and should not affect the interaction of VPC-13566 with the protein
Summary
The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. The AR substitution T878A, identified in the LNCaP cell line, confers resistance to the antiandrogen hydroxyflutamide [14] and is promiscuously activated by progesterone and 17β-estradiol [15] Other mutations such as W742C/L and F877L are associated with resistance to the anti-androgens bicalutamide [16,17,18] and enzalutamide [19,20,21], respectively. Identification and characterization of resistance-associated AR mutations, as biomarkers for primary treatment of both naïve PCa and CRPC patients, are critically important for predicting, as well as monitoring, patient’s response to therapy This process is essential for the development of evidence-based precision oncology
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