SPOP mutations increase PARP inhibitor sensitivity via CK2/PIAS1/SPOP axis in prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Impaired DNA damage repair (DDR) in prostate cancer (PCa) increases sensitivity to PARP inhibitors, but mechanisms are unclear.
• Genomic instability is a hallmark of cancer, particularly in PCa.
• SPOP gene mutations are found in a subset of PCa cases.

Purpose of the Study:

• To elucidate the mechanism linking SPOP mutations, genomic instability, and PARP inhibitor sensitivity in PCa.
• To investigate the role of the CK2/PIAS1/SPOP axis in DDR and PCa cell response to olaparib.

Main Methods:

• Analysis of genomic instability in SPOP-mutated PCa cells.
• Assessment of olaparib-induced apoptosis in SPOP-mutated PCa cells.
• Investigation of CK2-mediated phosphorylation of PIAS1 and its effect on SPOP SUMOylation and E3 ligase activity.
• Evaluation of the CK2/PIAS1/SPOP axis in PCa models and patient-derived organoids.
• Testing SPOP inhibitor effects on DDR and olaparib sensitivity.

Main Results:

• SPOP-mutated PCa cells exhibit profound genomic instability and heightened sensitivity to olaparib.
• Olaparib induces CK2-mediated phosphorylation of PIAS1-S468, promoting SPOP SUMOylation and E3 ligase activity in DDR.
• Disruption of the CK2/PIAS1/SPOP axis, via SPOP mutations or impaired CK2 phosphorylation, leads to defective DDR.
• Impaired DDR enhances olaparib-induced apoptosis in PCa cells, improving olaparib sensitivity in preclinical models.

Conclusions:

• The CK2/PIAS1/SPOP signaling axis plays a critical role in regulating DDR in PCa.
• SPOP mutations or defects in this axis confer sensitivity to PARP inhibitors.
• Disruption of the CK2/PIAS1/SPOP axis serves as a potential biomarker for targeted PCa therapy with PARP inhibitors.