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Lorenzin et al. J Transl Genet Genom 2019;3:5. I https://doi.org/10.20517/jtgg.2019.01 Page 5 of 12

suggesting an evolutionary advantage for more aggressive disease. AR-V7 is significantly over-expressed
in antiandrogen resistant tumors [52,57,58] and its expression is associated with resistance to abiraterone and
enzalutamide in two cohorts of CRPC patients [59,60] . This observation was recently confirmed in independent
patients cohorts [61,62] . Moreover, AR-V7 nuclear expression in circulating tumor cells was suggested as
treatment-specific biomarker for metastatic CRPC (mCRPC) patients with short survival upon enzalutamide
and abiraterone treatment and increased survival benefit on taxane therapy compared to AR-targeted
therapy [63,64] . However, a recent report did not support the predictive role of AR-V7 and AR-V9 detection in
[65]
the circulation .

A direct link for AR-V7-induced resistance to enzalutamide was provided by the restoration of sensitivity
[66]
to antiandrogens in 22Rv1 cells depleted of AR-V7 . In this model AR-V7 seems to fully compensate for
AR-FL function, yet other models expressing AR-V7 or other AR-Vs, such as VCaP cells, remain sensitive
to androgen depletion and antiandrogens; furthermore, the growth promoting effect of AR-Vs remains
dependent on AR-FL [7,67] . Recent papers investigated the genomic binding of AR-FL and AR-V7 in CRPC
cells and identified AR-FL and AR-V7 co-bound sites preferentially at ARE within enhancers. Interestingly,
an additional subset of genes was bound and regulated uniquely by AR-V7 [68,69] . ZFX represents a crucial
partner for AR-V7 binding at promoters, and the non-canonical gene expression program regulated by the
[68]
two transcription factors promotes malignant growth of CRPC cells and is associated with poor prognosis .

Other mechanisms of resistance to ADT and AR-targeted therapies relying on AR and/or its regulated
targets involve (1) maintenance of physiological intratumoral androgen levels, (2) dysregulated expression
and/or mutation of AR cofactors, and (3) cross-regulation of AR targets by other nuclear receptors.

Following castration the levels of testosterone in circulation drop by > 90%. However the adrenal androgens
dehydroepiandrosterone (DHEA) and androstenedione can serve as substrates for testosterone and DHT
synthesis in the prostate replenishing the pool of androgens needed by the tumor cells [70,71] . Furthermore,
a gain-of-function mutation in the HSD3B1 gene was described in CRPC patients and in cell lines, such as
LNCaP and VCaP, as increasing the stability of the enzyme and thereby enhancing the conversion of DHEA
[72]
to intratumoral DHT .
Beside mutations and structural rearrangements affecting the AR locus itself, aberrations of other genes
modulating the AR signaling pathway have been observed in metastatic disease [18,19,22,23] . These include point
[73]
mutations and amplifications of the pioneer factor FOXA1 in 10%-20% of mCRPC patients , amplifications/
[74]
gains and mutations of the AR coactivator NCOA2 , mutations and deletions in ZBTB16, NCOR1 or
NCOR2, known AR corepressors [19,75] .

Preclinical studies and indirect evidence support the hypothesis that other nuclear receptors [e.g.,
glucocorticoid receptor (GR), progesterone receptor (PGR) and mineralcorticoid receptor] could substitute
[76]
AR in gene regulation given the shared structure and the high homology of the DNA-binding domain .
Indeed, upregulation of and dependence on GR were observed in LNCaP xenograft models resistant to
enzalutamide. Moreover, it was shown that AR and GR have similar cistromes and that GR overexpression
mediates the induction of a subset of AR target genes thought to be involved in resistance [77,78] . More
indirectly, in clinical cohorts of primary prostate cancers shorter relapse free survival was associated with
[79]
high expression of PGR in situ .

GENOMIC FEATURES OF AR-INDEPENDENT RESISTANCE
Lineage plasticity is recognized as one possible mechanism to evade targeted therapy where cancer cells
transition towards an alternative cell lineage that is not dependent on the target. This mechanism is active
in a fraction of CRPCs under AR-targeted drugs pressure. Since the introduction of second generation