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<p>Although PARP1/2 inhibitors have been FDA-approved for the treatment of BRCA-mutated pancreatic cancer, their clinical application remains limited due to the high prevalence of BRCA-proficient cases. Previous studies have shown that IDO can modulate tumor cell sensitivity to PARP1/2 inhibition. However, the mechanism underlying their synergistic effects in pancreatic cancer therapy remain unclear. This study aimed to investigate the synergistic antitumor effects of dual IDO1 and PARP1/2 inhibition in BRCA-proficient pancreatic cancer cell lines and to elucidate the underlying mechanisms. In this study, we selected the IDO1 inhibitor Epacadostat and the PARP1/2 inhibitor Olaparib, which were used to treat BRCA-proficient SW1990 and CFPAC-1 cell lines at different concentrations. The effects on cell cytotoxicity were evaluated using the MTT assay. Intracellular levels of NAD<sup>+</sup>, kynurenine, and reactive oxygen species (ROS) were measured using commercial kits. DNA damage was assessed by comet assay, while apoptosis was assessed through flow cytometry. Additionally, an SW1990 xenograft model was employed to evaluate the in <i>vivo</i> antitumor efficacy of Epacadostat and Olaparib, alone or in combination. The expression of BRCA1, Rad51, and γH2AX was detected by immunohistochemistry, Western blot, and immunofluorescence. Our results demonstrate that Epacadostat and Olaparib significantly reduced the proliferation of BRCA-proficient pancreatic cancer cell lines SW1990 and CFPAC-1. In combination treatment, Epacadostat significantly decreased levels of kynurenine and NAD<sup>+</sup>, which enhanced PARP-mediated DNA damage. Moreover, Epacadostat and Olaparib synergistically increased cellular ROS levels, leading to oxidative DNA damage. In <i>vivo</i> experiments further revealed that the combination of Olaparib and Epacadostat significantly suppressed SW1990 tumor growth compared to the monotherapy group, while also promoting increased γH2AX expression without causing weight loss. Importantly, Olaparib and Epacadostat significantly inhibited the expression of homologous recombination (HR) core proteins, such as BRCA1 and Rad51, which may impair DNA repair by the HR pathway. Taken together, these findings suggest that simultaneous targeting of IDO1 and PARP1/2 may represent a promising therapeutic strategy for the broader population of patients with BRCA-proficient pancreatic cancer.</p>

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Epacadostat and Olaparib synergistically inhibit pancreatic cancer growth through downregulation HR-associated proteins

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Lei Huang,
  • Ye Yang,
  • Zhengzhen Chen,
  • Li Dai,
  • Jialu Shao,
  • Bingjun Qian

摘要

Although PARP1/2 inhibitors have been FDA-approved for the treatment of BRCA-mutated pancreatic cancer, their clinical application remains limited due to the high prevalence of BRCA-proficient cases. Previous studies have shown that IDO can modulate tumor cell sensitivity to PARP1/2 inhibition. However, the mechanism underlying their synergistic effects in pancreatic cancer therapy remain unclear. This study aimed to investigate the synergistic antitumor effects of dual IDO1 and PARP1/2 inhibition in BRCA-proficient pancreatic cancer cell lines and to elucidate the underlying mechanisms. In this study, we selected the IDO1 inhibitor Epacadostat and the PARP1/2 inhibitor Olaparib, which were used to treat BRCA-proficient SW1990 and CFPAC-1 cell lines at different concentrations. The effects on cell cytotoxicity were evaluated using the MTT assay. Intracellular levels of NAD+, kynurenine, and reactive oxygen species (ROS) were measured using commercial kits. DNA damage was assessed by comet assay, while apoptosis was assessed through flow cytometry. Additionally, an SW1990 xenograft model was employed to evaluate the in vivo antitumor efficacy of Epacadostat and Olaparib, alone or in combination. The expression of BRCA1, Rad51, and γH2AX was detected by immunohistochemistry, Western blot, and immunofluorescence. Our results demonstrate that Epacadostat and Olaparib significantly reduced the proliferation of BRCA-proficient pancreatic cancer cell lines SW1990 and CFPAC-1. In combination treatment, Epacadostat significantly decreased levels of kynurenine and NAD+, which enhanced PARP-mediated DNA damage. Moreover, Epacadostat and Olaparib synergistically increased cellular ROS levels, leading to oxidative DNA damage. In vivo experiments further revealed that the combination of Olaparib and Epacadostat significantly suppressed SW1990 tumor growth compared to the monotherapy group, while also promoting increased γH2AX expression without causing weight loss. Importantly, Olaparib and Epacadostat significantly inhibited the expression of homologous recombination (HR) core proteins, such as BRCA1 and Rad51, which may impair DNA repair by the HR pathway. Taken together, these findings suggest that simultaneous targeting of IDO1 and PARP1/2 may represent a promising therapeutic strategy for the broader population of patients with BRCA-proficient pancreatic cancer.