Androgen receptor mutations
CRPC patients could be resistant to Enz because of AR mutations. The
majority of mutations occur in the LBD (Snow, Lallous et al., 2019).
Molecular dynamics simulations and molecular mechanics based on
generalized Born surface area calculations have validated that helix 12
(H12) functions as a cover at the top of AR LBD.
Under normal
circumstances, the C-ring of Enz is near H12,
leading to the closing of H12 and the distortion of the
coactivator-binding site. When the C-ring of Enz is located near helix
H11 or loop 11-12, H12 tends to serve as an auxiliary activator-binding
site to promote transcription. Interestingly, in this case, Enz switches
to become an AR agonist (Liu, Wang et al., 2017). For instance, the AR
F876L mutation was previously found to convert the AR antagonist Enz to
an AR agonist (Korpal, Korn et al., 2013). In this respect, the AR
degradation enhancer ASC-J9® directly targets AR
F876L, mediating the degradation of this mutant (Wang, Lin et al.,
2016). In addition, a novel AR antagonist, JJ-450, inhibited the
translocation and function of the AR F876L mutant, which suggests a new
potential strategy for Enz-resistant CRPC treatment (Wu, Wang et al.,
2020). Other studies incorporating the detection of circulating
cell-free DNA showed that the F877L, H875Y, T878A/D891H, and T878A/S889G
AR mutations can lead to altered Enz functions. In particular, the
double mutant F877L/T878A converted Enz into a fully functional agonist.
The AR antagonist darolutamide (ODM-201), which is focused on AR
mutants, significantly suppressed the transcriptional activity of the
F877L, H875Y/T878A, F877L/T878A, and T878G mutants (Prekovic, Van et
al., 2016 , Borgmann, Lallous et al., 2018 , Lallous, Volik et al.,
2016).
Glucocorticoid
receptor overexpression
The glucocorticoid receptor (GR) is one of the members of a class of
nuclear steroid receptors. The expression of GR is upregulated after Enz
treatment, which contributes to the re-expression of approximately 50%
of the AR-responsive genes. Several canonical AR target genes have not
been shown to be regulated by GR, including KLK3 and TMPRSS2. AR and GR
have highly homologous DBDs and overlapping transcriptomes and
cistromes. AR directly represses GR
expression via a negative androgen response element (ARE) in the
GR promoter. Consequently, upon exposure to the AR inhibitor Enz, the
inhibition of GR expression is abrogated. The GR agonist dexamethasone
is sufficient to make patients resistant to Enz, while GR antagonists
can restore sensitivity (Arora, Schenkein et al., 2013).
GR plays a critical role in humans, and completely blocking GR is
incompatible with life. Li et al. (Li, Alyamani et al., 2017) focused on
the tumour metabolic switch associated with GR activation. They
demonstrated that Enz-resistant prostate cancer cells sustained cortisol
concentrations due to the loss of 11β-hydroxysteroid dehydrogenase-2
(11β-HSD2) and the impaired
conversion to cortisone. As a result, GR was inhibited, and
glucocorticoid-dependent signalling was
activated. Moreover, ubiquitin
E3-ligase autocrine mobility factor receptor
(AMFR) mediated the loss of
11β-HSD2, leading to Enz resistance. In a genome-wide CRISPR-Cas9
screening study (Palit, Vis et al., 2019), researchers found that the
loss of transducin-like enhancer of split 3 (TLE3) in conjunction with
AR inhibition by the GR enhancer resulted in GR upregulation, which led
to Enz resistance in LNCaP cells. Hence,
TLE3 was involved in the
regulation of GR expression and drug resistance, providing a novel
target for Enz-resistant CRPC treatment. Considering the increase in GR
upon AR inhibition, Remi M et al. (Adelaiye-Ogala, Gryder et al., 2020)
demonstrated that inhibiting the phosphatidylinositol 3-kinase/ protein
kinase B (PI3K/AKT) pathway can block GR expression and activity after
AR inhibition, overcoming GR-mediated resistance to Enz.
It was reported that BET
bromodomain inhibition,
pyrrole-imidazole polyamide, and selective glucocorticoid receptor
modulators could inhibit GR expression and GR-regulated
proliferation-associated genes for Enz-resistant CRPC treatment (Shah,
Wang et al., 2017 , Kurmis, Yang et al., 2017 , Kach, Long et al.,
2017). Recently, Wu et al. (Wu, Xie et al., 2019) utilized a rational
drug design method to analyse the chemical
structures of the anti-androgen and crystal structure of GR. They
developed GR/AR dual antagonists
by virtual screening and biological evaluation. After performing a
bioassay, they found that the dual antagonist
Z19 inhibited the
transcriptional activity of both
AR and GR, reducing the protein and mRNA levels of the downstream
proteins of GR and AR signalling (PSA for AR and KLF9 for GR). This
rational drug design provides an efficient strategy for the development
of novel agents for Enz-resistant CRPC