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

Masaru Tani1, Koji Hatano1, Yu Ishizuya1

  • 1Department of Urology, The University of Osaka Graduate School of Medicine, Suita, Japan.

Cancer Science
|September 16, 2025
PubMed
Summary
This summary is machine-generated.

Researchers identified Ligase 1 (LIG1) as a novel synthetic lethal target in prostate cancer. Combining LIG1 and poly (ADP-ribose) polymerase (PARP) inhibitors shows promise for treating metastatic castration-resistant prostate cancer.

Keywords:
CRISPR‐Cas9 knockout screeningLIG1 inhibitorsPARP inhibitorprostate cancersynthetic lethality

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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.