Olaparib Combined with Anti-PD1 Enhances Immunotherapy of Gastric Cancer Via NF-κB/c-Myc/PD-L1 Signaling

Dig Dis Sci. 2025 Jun;70(6):2032-2042. doi: 10.1007/s10620-025-09021-y. Epub 2025 Apr 16.

Abstract

Background: PARP inhibitors, effective in BRCA-mutated cancers, show potential in gastric cancer (GC) where homologous recombination defects (e.g., BRCA1/2 mutations) are common. Olaparib, a PARP inhibitor, upregulates PD-L1, suggesting synergy with PD-1 inhibitors for enhanced GC therapy.

Methods: Using CCK-8 screening of 867 drugs, olaparib demonstrated potent GC cell inhibition. Western blot and qRT-PCR assessed PD-L1, c-MYC, COX-2, and NF-κB pathway proteins (p65/p-p65). Functional assays (Transwell, wound healing, colony formation) evaluated olaparib's effects on GC cell proliferation, migration, and invasion. A GC mouse model tested olaparib combined with anti-PD1. TCGA and Kaplan-Meier analyzed PARP expression-prognosis correlations.

Results: Olaparib suppressed GC cell proliferation, migration, and invasion in vitro. Western blot revealed upregulated c-MYC, COX-2, p65, p-p65, and PD-L1, confirmed by qRT-PCR for PD-L1. Low PARP expression correlated with better GC patient survival. In vivo, olaparib synergized with anti-PD1 to enhance tumor suppression.

Conclusion: Olaparib activates the NF-κB/c-MYC pathway to elevate PD-L1, supporting its combination with PD-1 inhibitors as a promising GC therapeutic strategy.

Keywords: Gastric cancer (GC); Immunotherapy; Olaparib; PARP; PD-L1.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols* / pharmacology
  • B7-H1 Antigen* / genetics
  • B7-H1 Antigen* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Humans
  • Immune Checkpoint Inhibitors* / pharmacology
  • Immunotherapy* / methods
  • Mice
  • Mice, Nude
  • NF-kappa B* / metabolism
  • Phthalazines* / pharmacology
  • Phthalazines* / therapeutic use
  • Piperazines* / pharmacology
  • Piperazines* / therapeutic use
  • Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor* / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction / drug effects
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / immunology
  • Stomach Neoplasms* / metabolism
  • Stomach Neoplasms* / pathology
  • Xenograft Model Antitumor Assays

Substances

  • olaparib
  • Phthalazines
  • Piperazines
  • B7-H1 Antigen
  • NF-kappa B
  • CD274 protein, human
  • Proto-Oncogene Proteins c-myc
  • Immune Checkpoint Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • MYC protein, human
  • Programmed Cell Death 1 Receptor