PARP inhibitor augments anti-tumor efficacy of DNMT inhibitor in cholangiocarcinoma

Cholangiocarcinoma (CCA) is a dismal, heterogeneous malignancy with limited treatment options. One of the key epigenetic dysregulations in CCA is aberrant DNA methylation, suggesting that targeted DNA methylation is a promising therapeutic strategy for this disease. However, the clinical utility of DNA demethylation reagents is not well documented. Here, we established patient-derived CCA cell lines and demonstrated that the demethylating agents decitabine and 5-azacytidine had minimal effects on antitumor proliferation of CCA cells. A combinatorial drug screen using a kinase inhibitor library identified PARP inhibitors as sensitizers that synergistically enhanced the antitumor effects of decitabine. The combination of DNMT inhibitors and PARP inhibitors significantly blocks tumor growth in both CCA patient-derived xenograft models and the somatic CCA model induced by hydrodynamic tail vein injection. Transcriptomic profiling analysis showed that the combination treatment activated the inflammatory signaling pathway and upregulated senescence-associated secretory phenotype gene expression, resulting in genomic instability in CCA. Mechanistically, combination treatment disrupted XRCC1 function and increased PARP1 trapping, leading to persistent DNA damage and senescence. Together, our study provides a preclinical proof-of-concept for the use of DNMT inhibitors in combination with PARP inhibitors as a novel therapeutic strategy and potentially optimizes current clinical practice in the treatment of CCA.