Development of a Synthetic Lethality-Based Combination Therapy Using LIG1 and PARP Inhibitors for Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease despite current therapies.
• Resistance to poly (ADP-ribose) polymerase inhibitors (PARPIs) limits their efficacy, particularly in patients without homologous recombination repair deficiencies.
• Novel therapeutic strategies targeting synthetic lethal interactions are needed to improve treatment outcomes for mCRPC.

Purpose of the Study:

• To identify novel genes that confer sensitivity or resistance to PARPIs in prostate cancer.
• To investigate the potential of Ligase 1 (LIG1) as a synthetic lethal target in combination with PARP inhibition.
• To evaluate the therapeutic efficacy and safety of combining LIG1 and PARP inhibitors for mCRPC treatment.

Main Methods:

• Genome-wide CRISPR-Cas9 knockout screening in multiple prostate cancer cell lines (DU145, 22Rv1, LNCaP) to identify genes affecting olaparib sensitivity.
• In vitro assessment of DNA damage, apoptosis, and drug synergy upon combined inhibition of LIG1 and PARP.
• In vivo validation of the combination therapy in a prostate cancer xenograft model.
• Immunohistochemical analysis of LIG1 expression in clinical prostate cancer tissues.

Main Results:

• Genome-wide screening identified LIG1 as a synthetic lethality-inducing factor and TP53 as a resistance factor to PARPIs.
• Simultaneous inhibition of LIG1 and PARP significantly increased DNA damage and apoptosis in prostate cancer cells.
• The combination of LIG1 inhibitor L82-G17 with olaparib demonstrated synergistic effects and suppressed tumor growth in vivo with minimal toxicity.
• LIG1 was found to be overexpressed in castration-resistant prostate cancer (CRPC) tissues.

Conclusions:

• LIG1 is a novel synthetic lethality-inducing factor in prostate cancer, offering a new therapeutic target.
• The combination of PARP and LIG1 inhibitors, such as olaparib and L82-G17, enhances anti-tumor efficacy irrespective of BRCA mutation status.
• This combination therapy represents a promising novel therapeutic strategy for mCRPC, potentially expanding treatment options for a wider patient population.