©TheCanadian Journal ofUrology™: International Supplement, April 2014
mechanisms
33-35
such as AR amplification
36,37
and
local androgen production,
38
androgen independent
and AR dependent mechanisms
39,40
such as AR
mutations
41-44
and ligand independentARactivation,
45-57
aswell asandrogenandAR independentmechanisms
such as alternative survival pathways.
58-61
Ligand-
independentAR activation is postulated to eventuate
from overexpression, mutation or, most commonly,
truncationof the ligand-bindingC-terminusofAR.
62-65
Loss of theC-terminus results in splicevariants ofAR
that canbe constitutively active. This likely occurs in
about 25%ofCRPCpatients.
54,66
ARdiffers fromother
steroid receptors in that the transcriptional activity is
mainly through the activation function region 1 in the
N-terminal domain rather than in the ligand-binding
domain.
67
Therefore treatment of splice variants
requiringtargetingoftheN-terminustodatehas lacking
pharmacological success. Andersen and colleagues
havereportedthatEPI-001,amarinespongederivative,
can inhibit transactivation of the N-terminal domain
and block induction of androgen-regulated genes.
68
Recently it was reported that long non-coding RNAs
regulate activation of both truncated and full-length
AR, leading to ligand-independentactivationof theAR
transcriptionalprogram.
69
Targeting theN-terminus is
importantandnewapproaches to inhibitARarebeing
developed.
Tumor-related factors proposed to contribute to
castrationresistancearestemcells
70,71
and intratumoral
androgens,
72,73
Table 1. High levels of androgens in
10
Thechanging landscapeofadvancedandcastrationresistantprostatecancer: latestscienceandreviseddefinitions
TABLE 1.
Possiblemolecularmechanismsof castration resistance (not exhaustive)
Strategy/pathway
Mechanisms/references
Increased androgen sensitivity
• ARgene amplification
36,37
• AR stabilization
33
• Increased local androgenproduction
(e.g. increased conversionof testosterone toDHT)
38
• Androgen transport
34,35
Aberrant activationof theAR/promiscuity
• ARmutations
41-44
ofAR (inappropriateAR activationby
• Alterations inAR coregulators
39,40
non-androgen steroids and androgen antagonists)
Ligand independentAR activation/
• ActivationofARbygrowth factors (IGF-1, KGF, EGF)
48
alteredAR transcriptional activity
• Receptor-tyrosine-kinase activatedpathway (HER-2/
neu signaling cascade; Srckinase)
46,47,52,57
• AKTpathway
50,51
• E2C (UBE2C)
55
• UpregulationofAR (Rb/E2F/nuclear receptor axis;
AR actionon enhancer versus suppressor elements)
45,53
• AR splicevariants (ligand-binding-domaindeficient)
49,54-56
• lncRNA-dependentmechanisms of androgen-receptor-
regulatedgene activationprograms
69
AR independent pathways
• Overexpressionof oncogenes (BCL2gene)
58-61
(activationof parallel survival pathways)
Stem cells
• Androgen-independencebefore initiationof androgen
deprivation therapy
70,71
Intratumoral androgens
• Alternative intratumoral steroidbiosynthesispathway
73
• Fatty acids induced androgen synthesis
72
AR= androgen receptor; DHT=dihydrotestosterone; IGF-1 = insulin-like-growth factor 1; KGF= keratinocyte growth factor;
EGF= epidermal growth factor; BCL2=B-cell lymphoma2;UBE2C=ubiquitin-conjugating enzymeE2Cgene; lncRNA= long
non-codingRNA)
