Arp2/3 Inhibition Synergizes With PARP Inhibitors by Impairing Homologous Recombination in Gastric Cancer Cells.

Authors

Wenlong Li, Xinyue Pei, Yongpei Li, Yanji Lu, Xian Hong, Ming Sui, Qiang Li, Xueying Sun, Jingqiu Wang, Enming Zhang, Yihan Liu, Tao Wang, Jing Xu, Zhihui Deng

Published in

Frontiers in bioscience (Landmark edition). Volume 31. Issue 7. Pages 51619. Jul 17, 2026.

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown limited efficacy in gastric cancer, primarily due to the rarity of inherent homologous recombination (HR) deficiency. The nuclear Arp2/3 complex was recently implicated in DNA double-strand break repair via HR. Here, we investigate whether pharmacological inhibition of Arp2/3 can induce a functional HR-deficient state to synergize with PARPi in gastric cancer cells.
HR repair efficiency was assessed using a direct repeat green fluorescent protein (DR-GFP) reporter assay in HEK-293T cells following Arp2/3 inhibition with CK666, siRNA-mediated knockdown, or CRISPR/Cas9-mediated knockout of ACTR2/ACTR3. HGC-27 and AGS gastric cancer cells were treated with CK666 alone and in combination with olaparib or niraparib. Cell viability and synergy were evaluated by Cell Counting Kit-8 (CCK-8) and clonogenic assays (n = 3 independent experiments). DNA damage and apoptosis were assessed by immunofluorescence for gamma H2A histone family member X (γH2AX) foci (≥100 cells per condition) and Western blot analysis for cleaved PARP.
Arp2/3 inhibition with CK666 significantly impaired HR repair efficiency in the DR-GFP assay (p < 0.01). This effect was recapitulated by genetic knockdown or knockout of ACTR2/ACTR3. CK666 alone exerted minimal cytotoxicity, but synergized with both olaparib and niraparib to suppress proliferation (Combination Index <1), reducing the half-maximal inhibitory concentration (IC₅₀) of PARPi by approximately threefold. Combination treatment markedly enhanced γH2AX foci formation (p < 0.0001) and increased the level of cleaved PARP compared with either monotherapy.
Inhibition of Arp2/3 compromises HR repair capacity, thereby creating a synthetic lethal interaction with PARP inhibition in gastric cancer cells. This combination strategy represents a promising therapeutic approach to broaden the clinical utility of PARPi in HR-proficient tumors and may also enable dose reduction to mitigate associated toxicities.

PMID:
42530272
Bibliographic data and abstract were imported from PubMed on 30 Jul 2026.

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