Simple Summary Ligand-independent androgen receptor splice variants emerge during
androgen deprivation therapy and are suspected to render prostate carcinomas castration-resistant.
In a retrospective analysis of a large cohort of primary and advanced prostate tumors,
we observed increased expression of androgen receptor splice variants in therapy refractory
tumors. Our hypothesis was that AR splice variants exert their tumor-promoting activity
by modulating the intrinsic DNA repair machinery. In the sequence from primary over
advanced tumors under androgen-deprivation therapy to castration resistance, AR splice
variant expression increases and is linked to increased expression of DNA repair genes.
This effect of AR splice variants appeared independent of their known impact on tumor
cell proliferation. These clinical findings were validated in an androgen-sensitive
prostate cancer cell line that mimics a castration-resistant phenotype by overexpression
of AR-V7. Modulated DNA repair gene expression in the presence of AR splice variants
is linked to increased DNA repair activity, pointing at a novel therapeutic approach
for castration-resistant prostate cancer. Background: Canonical androgen receptor
(AR) signaling regulates a network of DNA repair genes in prostate cancer (PCA). Experimental
and clinical evidence indicates that androgen deprivation not only suppresses DNA
repair activity but is often synthetically lethal in combination with PARP inhibition.
The present study aimed to elucidate the impact of AR splice variants (AR-Vs), occurring
in advanced or late-stage PCA, on DNA repair machinery. Methods: Two hundred and seventy-three
tissue samples were analyzed, including primary hormone-naive PCA, primary metastases,
hormone-sensitive PCA on androgen deprivation therapy (ADT) and castration refractory
PCA (CRPC group). The transcript levels of the target genes were profiled using the
nCounter platform. Experimental support for the findings was gained in AR/AR-V7-expressing
LNCaP cells subjected to ionizing radiation. Results: AR-Vs were present in half of
hormone-sensitive PCAs on androgen deprivation therapy (ADT) and two-thirds of CRPC
samples. The presence of AR-Vs is highly correlated with increased activity in the
AR pathway and DNA repair gene expression. In AR-V-expressing CRPC, the DNA repair
score increased by 2.5-fold as compared to AR-V-negative samples. Enhanced DNA repair
and the deregulation of DNA repair genes by AR-V7 supported the clinical data in a
cell line model. Conclusions: The expression of AR splice variants such as AR-V7 in
PCA patients following ADT might be a reason for reduced or absent therapy effects
in patients on additional PARP inhibition due to the modulation of DNA repair gene
expression. Consequently, AR-Vs should be further studied as predictive biomarkers
for therapy response in this setting.
