Androgen receptor splicing variant 7 (ARv7) promotes DNA damage response in prostate cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen deprivation therapy (ADT) combined with radiotherapy is standard for locally advanced prostate cancer (PCa).
• Androgen receptor splicing variants (ARvs) may confer resistance to ADT by activating compensatory DNA damage response (DDR) pathways.
• The precise role and mechanism of ARvs in DDR and treatment resistance remain unclear.

Purpose of the Study:

• To investigate the role of AR splicing variant 7 (ARv7) in regulating the DNA damage response (DDR) in prostate cancer (PCa) cells.
• To elucidate the mechanism by which ARv7 influences DDR pathways and treatment resistance.
• To assess ARv7 as a potential predictive biomarker for novel therapeutic strategies.

Main Methods:

• Utilized ionizing radiation (IR) and doxorubicin (Dox) to induce DNA damage in PCa cell models.
• Investigated the effect of ARv7 on homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways.
• Assessed the impact of ARv7 on the efficacy of AR antagonists combined with poly ADP-ribose polymerase (PARP) inhibitors.

Main Results:

• ARv7 significantly enhanced DDR in PCa cells under DNA damage, independent of the canonical androgen receptor (AR).
• ARv7 upregulated both HR and NHEJ pathways by forming a regulatory loop with PARP1.
• ARv7 presence diminished the synergistic effect of AR antagonists and PARP inhibitors, impacting treatment efficacy.

Conclusions:

• Constitutively active ARv7 contributes to radioresistance in PCa following ADT.
• ARv7 may serve as a predictive biomarker for evaluating the effectiveness of PARP inhibitor-based therapies in PCa.
• Understanding ARv7's role is crucial for overcoming treatment resistance in advanced prostate cancer.