Androgen deprivation therapy (ADT) considerably increases the efficacy of radiation in the treatment of patients with locally advanced prostate cancer (PCa) by decreasing the DNA damage response (DDR) pathway. However, recent research has raised the possibility that certain patients may resist this combo therapy because androgen receptor splicing variations (ARvs) may initiate a compensatory DDR pathway when conventional androgen receptor (AR) signaling is blocked.
However, it was unclear how exactly various ARvs control the DDR and the precise mechanisms by which they do so. By employing cell models exposed to ionizing radiation (IR) and doxorubicin (Dox), researchers were able to show that AR splicing variation 7 (ARv7) the most prevalent type of ARvs, strongly accelerated the DDR of PCa cells under severe DNA damage irrespective of its parental AR. Furthermore, by building a positive regulatory loop with poly ADP-ribose polymerase 1 (PARP1), ARv7 is sufficient to upregulate both the homologous recombination (HR) and the nonhomologous end joining (NHEJ) pathways. Additionally, the synergistic impact of AR antagonists and PARP inhibitors, which had recently been demonstrated to be a potential future therapeutic approach for metastatic castration-resistant prostate cancer, was compromised by the presence of ARv7 (mCRPC).
Taking all of the information into account, it can be said that constitutively active ARv7 not only contributes to radioresistance following ADT but also has the potential to be a predictive biomarker for determining the effectiveness of innovative PARP inhibitor-based treatment for PCa.
Reference: faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202200190R
