2. Academic Validation
  3. DNA damage response mutations enhance the antitumor efficacy of ATR and PARP inhibitors in cholangiocarcinoma cell lines

DNA damage response mutations enhance the antitumor efficacy of ATR and PARP inhibitors in cholangiocarcinoma cell lines

  • Oncol Lett. 2025 Jan 7;29(3):128. doi: 10.3892/ol.2025.14874.
Tassanee Lerksuthirat 1,  Sunisa Prasopporn 2,  Rakkreat Wikiniyadhanee 3,  Sermsiri Chitphuk 1,  Wasana Stitchantrakul 1,  Paravee Owneium 3,  Siwanon Jirawatnotai 2,  Donniphat Dejsuphong 3
Affiliations

Affiliations

  • 1 Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
  • 2 Siriraj Center of Research for Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
  • 3 Program in Translational Medicine, Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samutprakarn 10540, Thailand.
PMID: 39822940 DOI: 10.3892/ol.2025.14874
Abstract

Cholangiocarcinoma (CCA) is a biliary tract carcinoma that is challenging to treat due to its heterogeneity and limited treatment options. Genetic alterations in DNA damage response (DDR) pathways and homologous recombination (HR) defects are common in CCA. This has prompted interest in the use of ataxia telangiectasia and Rad3-related protein (ATR) and poly(ADP-ribose) polymerase (PARP) inhibitors to treat CCA. The present study investigated the impact of an ATR Inhibitor and various PARP inhibitors, individually and in combination, on CCA cell lines with different DDR mutation profiles. DDR gene alterations in these cell lines were analyzed, and the responses of the cells to treatment with the PARP inhibitors olaparib, veliparib and talazoparib and/or the ATR Inhibitor AZD6738 were evaluated. Assessments focused on cellular viability, clonogenic survival and the combination index, alongside changes in DNA damage assessed via the formation of micronuclei and γ-H2A histone family member X foci. The results revealed that the CCA cell lines with more DDR mutations exhibited greater sensitivity to single and combination treatments. Talazoparib was found to be the most potent PARP Inhibitor in the CCA cell lines. The combination of AZD6738 and talazoparib demonstrated varying synergistic effects depending on the genetic background of the CCA cells, with greater efficacy in the cell lines less sensitive to single drug treatments. Mechanistically, this combination promoted the accumulation of DNA damage, including DNA double-strand breaks. Overall, the study underscores the importance of HR in CCA. It reveals an association between the extent of DDR mutations and the response to AZD6738 and PARP inhibitors in CCA, both as single agents and in combination. These findings highlight that the number of mutated genes influences variability in the drug response.

Keywords

ATR inhibitor; DNA damage response; PARP inhibitor; biliary tract cancer; cholangiocarcinoma; combination index; drug combination.

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