Stress-induced CD55 supports homologous recombination capacity and drives oxaliplatin resistance in colorectal cancer.

backgroundAcquired resistance to oxaliplatin limits the efficacy of first-line chemotherapy in colorectal cancer (CRC), yet the stress-responsive signaling mechanisms that enable tumor cells to adapt to platinum-induced DNA damage remain incompletely understood. CD55, a glycosylphosphatidylinositol-anchored complement regulator, has recently been implicated in non-canonical cellular stress signaling beyond its classical immune-modulatory role. Here, we investigated whether stress-induced CD55 signaling contributes to oxaliplatin resistance by modulating DNA damage response and repair capacity.

methodsOxaliplatin-resistant CRC cell lines were established through stepwise dose escalation. RNA sequencing with cross-validation against public datasets was used to identify candidate resistance genes. CD55 function was assessed using knockdown and overexpression approaches across seven CRC cell lines. Clinical correlations were evaluated using TCGA and GEO datasets. Homologous recombination (HR) capacity was measured using the DR-GFP reporter system, and DNA damage dynamics were assessed by γ-H2AX foci formation and comet assays. Drug interactions between oxaliplatin and PARP inhibitors were analyzed using the Chou-Talalay method. In vivo efficacy was evaluated in xenograft models.

resultsCD55 was consistently upregulated in oxaliplatin-resistant CRC cells across three independent datasets and was induced by oxaliplatin treatment in a dose- and time-dependent manner, with stress-associated nuclear translocation observed following DNA damage. CD55 depletion sensitized all seven CRC cell lines to oxaliplatin (approximately 1.2- to 5.4-fold), with at least one siRNA reaching statistical significance in every line, irrespective of microsatellite instability or p53 status. In patient cohorts, elevated CD55 expression predicted poor response to FOLFOX therapy and independently correlated with reduced disease-free survival (hazard ratio = 3.47). Mechanistically, CD55 expression inversely correlated with genomic instability markers, and CD55 depletion significantly reduced HR efficiency in both parental and oxaliplatin-resistant CRC cells (~ 40-46% reduction), impaired BRCA1 induction, and prolonged γ-H2AX accumulation. In oxaliplatin-resistant cells, CD55 depletion converted the antagonistic oxaliplatin-olaparib interaction toward synergy in a dose-ratio-dependent manner (synergistic at 3:1 and 1:3, additive at 1:1; mean CI 0.58-0.95), reaching significance at the 3:1 ratio (P = 0.025). In xenograft models, CD55 depletion combined with dual-agent treatment reduced tumor burden by 62.8% in HCT116-OXR and consistently across all treatment arms in HT29-OXR.

conclusionsCD55 acts as a stress-responsive signaling regulator that partially supports homologous recombination capacity under genotoxic stress and promotes oxaliplatin resistance in CRC. These findings identify CD55 as both a predictive biomarker and a therapeutic vulnerability, and demonstrate that CD55 depletion can induce a partial HR impairment - operationally described as a "BRCAness-like" state - that is sufficient to sensitize HR-proficient tumors to PARP inhibition, thereby expanding the potential utility of PARP inhibitor-based combination strategies.