目的：多聚腺苷二磷酸核糖聚合酶抑制剂（poly ADP-ribose polymerase inhibitors, PARP inhibitors）已成为卵巢癌维持治疗的重要手段,可显著延长患者生存期。然而,随着治疗的深入,部分患者逐渐表现出对PARP抑制剂的耐药性,这限制了其临床应用。如何提高卵巢癌患者对PARP抑制剂的敏感性并延缓耐药是临床亟需解决的问题。最新研究显示靶向铁死亡可增加卵巢癌细胞对PARP抑制剂的敏感性,有待进一步研究。方法：本研究采用生物信息学分析和药物预测模型,筛选与卵巢癌PARP抑制剂相关的铁死亡通路相关基因,敲减相关基因后检测PARP抑制剂尼拉帕利在卵巢癌细胞中的IC50。结果：生息分析和药物预测分析发现铁死亡相关基因CSF-1R和SLCO2B1与卵巢癌PARP抑制剂敏感性相关,且与患者预后显著相关。敲减CSF-1R和SLCO2B1影响卵巢癌细胞对PARP抑制剂尼拉帕利的敏感性。结论：靶向铁死亡相关基因CSF-1R和SLCO2B1可增强卵巢癌细胞对PARP抑制剂的敏感性。本研究为临床提供了扩大PARP抑制剂适应症、克服耐药性的新策略,为PARP抑制剂联合治疗方案提供了新的证据。
Abstract
Objective Poly (ADP-ribose) polymerase (PARP) inhibitors have become an important means of maintenance therapy for ovarian cancer, significantly extending patients' survival periods. However, as treatment progresses, some patients gradually develop resistance to PARP inhibitors, which limits their clinical application. Enhancing the sensitivity of ovarian cancer patients to PARP inhibitors and delaying resistance are urgent issues to be addressed in the clinic. Recent studies have shown that targeting ferroptosis can increase the sensitivity of ovarian cancer cells to PARP inhibitors, with the underlying mechanisms requiring further investigation. Methods This study utilized bioinformatics analysis and pharmacological prediction models to select genes related to the ferroptosis pathway that are associated with PARP inhibitors in ovarian cancer. After knocking down the relevant genes, we assessed the IC50 of the PARP inhibitor niraparib in ovarian cancer cells. Results Bioinformatics and drug prediction analyses identified ferroptosis-related genes CSF-1R and SLCO2B1 as being associated with ovarian cancer PARP inhibitor sensitivity and significantly correlated with patient prognosis. Knockdown of CSF-1R and SLCO2B1 affected the sensitivity of ovarian cancer cells to the PARP inhibitor niraparib. Conclusion Targeting ferroptosis-related genes CSF-1R and SLCO2B1 can enhance the sensitivity of ovarian cancer cells to PARP inhibitors. This study provides new strategies for expanding the indications of PARP inhibitors in the clinic, overcoming resistance, and offers new evidence for combination therapy regimens involving PARP inhibitors.
关键词
卵巢癌 /
PARP抑制剂 /
铁死亡 /
CSF-1R /
SLCO2B1
Key words
ovarian cancer /
PARP inhibitors /
ferroptosis /
CSF-1R /
SLCO2B1
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基金
湖南省自然科学基金“CSF-1R抑制剂促进铁死亡增强卵巢癌PARP抑制剂敏感性的作用与分子机制 ”（2023JJ60016）
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