Background: Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy in the United States with high grade serous ovarian cancer (HGSOC) as the most commonly diagnosed subtype. While therapies targeting deficiencies in the homologous recombination (HR) pathway are emerging as the standard treatment for HGSOC patients, this strategy is limited to the 50% of patients with a deficiency in this pathway. Therefore, patients with HR-proficient tumors are likely to be resistant to these therapies and require alternative strategies. Methods: Data from HGSOC patients in The Cancer Genome Atlas (TCGA) were analyzed for ATM status, ATM and PPARα expression, and used to perform Gene Set Enrichment Analysis (GSEA). Screening data from the Dependency Map were analyzed to identify FDA-approved drugs that preferentially inhibit ATM-low cancer cells. In vitro studies were performed to determine whether ATM inhibitors synergize with the PPARα agonist fenofibrate in HGSOC cell lines. Results: The HR gene Ataxia Telangiectasia Mutated (ATM) is wildtype in the majority of HGSOC patients and its kinase activity is upregulated compared to normal fallopian tube tissue. As high ATM has been associated with poor overall and progression-free survival, targeting ATM may be beneficial for a subset of HGSOC patients. Clinical trials of ATM inhibitors are commencing; however, ATM inhibitors are not effective as single agents. We aimed to explore novel therapeutic vulnerabilities of ATM deficient cells to develop a combinatorial therapy. Using data from TCGA, we found that multiple pathways related to metabolism are inversely correlated with ATM expression, suggesting that combining ATM inhibition and metabolic inhibition would be effective. Indeed, analysis of FDA-approved drugs from the Dependency Map demonstrated that ATM low cell lines are more sensitive to fenofibrate, a PPARα agonist that has been previously shown to affect multiple cellular metabolic pathways. Consistently, PPARα signaling is associated with ATM expression. We validated that combined inhibition of ATM and treatment with fenofibrate is synergistic in multiple HGSOC cell lines by inducing senescence. Conclusions: Our results suggest that metabolic changes induced by ATM inhibitors are a potential target for the treatment for HGSOC.

中文翻译：

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ATM抑制与非诺贝特在高级浆液性卵巢癌细胞中协同作用。

背景：上皮性卵巢癌（EOC）是美国最致命的妇科恶性肿瘤，其中以高度浆液性卵巢癌（HGSOC）为最常见的亚型。尽管针对同源重组（HR）途径缺陷的疗法正逐渐成为HGSOC患者的标准治疗方法，但该策略仅限于50％缺乏该途径的患者。因此，具有HR敏感型肿瘤的患者可能对这些疗法有抵抗力，并需要其他策略。方法：分析癌症基因组图谱（TCGA）中HGSOC患者的ATM状态，ATM和PPARα表达，并进行基因组富集分析（GSEA）。分析了从“依赖关系图”中筛选的数据，以识别出FDA批准的药物，该药物优先抑制低ATM癌细胞。进行了体外研究以确定ATM抑制剂在HGSOC细胞系中是否与PPARα激动剂非诺贝特协同作用。结果：HR基因共济失调毛细血管扩张症（ATM）在大多数HGSOC患者中均为野生型，与正常输卵管组织相比，其激酶活性上调。由于高ATM与不良的总体生存率和无进展生存率相关，因此靶向ATM对一部分HGSOC患者可能有益。ATM抑制剂的临床试验已经开始。但是，ATM抑制剂作为单药无效。我们旨在探索ATM缺陷细胞的新型治疗脆弱性，以开发组合疗法。使用TCGA的数据，我们发现与代谢相关的多种途径与ATM表达成反比，这表明将ATM抑制和代谢抑制相结合将是有效的。实际上，从Dependency Map对FDA批准的药物进行的分析表明，ATM低细胞株对非诺贝特（一种已被证明会影响多种细胞代谢途径的PPARα激动剂）更敏感。一致地，PPARα信号传导与ATM表达相关。我们证实，通过诱导衰老，在多种HGSOC细胞系中ATM抑制和非诺贝特联合治疗具有协同作用。结论：我们的结果表明，由ATM抑制剂诱导的代谢变化是治疗HGSOC的潜在目标。提示结合使用ATM抑制和代谢抑制将是有效的。实际上，从Dependency Map对FDA批准的药物进行的分析表明，ATM低细胞株对非诺贝特（一种已被证明会影响多种细胞代谢途径的PPARα激动剂）更敏感。一致地，PPARα信号传导与ATM表达相关。我们证实，通过诱导衰老，在多种HGSOC细胞系中ATM抑制和非诺贝特联合治疗具有协同作用。结论：我们的结果表明，由ATM抑制剂诱导的代谢变化是治疗HGSOC的潜在目标。提示结合使用ATM抑制和代谢抑制将是有效的。实际上，从Dependency Map对FDA批准的药物进行的分析表明，ATM低细胞株对非诺贝特（一种已被证明会影响多种细胞代谢途径的PPARα激动剂）更敏感。一致地，PPARα信号传导与ATM表达相关。我们证实，通过诱导衰老，在多种HGSOC细胞系中ATM抑制和非诺贝特联合治疗具有协同作用。结论：我们的结果表明，由ATM抑制剂诱导的代谢变化是治疗HGSOC的潜在目标。从Dependency Map对FDA批准的药物进行的分析表明，ATM低细胞株对非诺贝特（一种已被证明会影响多种细胞代谢途径的PPARα激动剂）更加敏感。一致地，PPARα信号传导与ATM表达相关。我们证实，通过诱导衰老，在多种HGSOC细胞系中ATM抑制和非诺贝特联合治疗具有协同作用。结论：我们的结果表明，由ATM抑制剂诱导的代谢变化是治疗HGSOC的潜在目标。从Dependency Map对FDA批准的药物进行的分析表明，ATM低细胞株对非诺贝特（一种已被证明会影响多种细胞代谢途径的PPARα激动剂）更加敏感。一致地，PPARα信号传导与ATM表达相关。我们证实，通过诱导衰老，在多种HGSOC细胞系中ATM抑制和非诺贝特联合治疗具有协同作用。结论：我们的结果表明，由ATM抑制剂诱导的代谢变化是治疗HGSOC的潜在目标。我们证实，通过诱导衰老，在多种HGSOC细胞系中ATM抑制和非诺贝特联合治疗具有协同作用。结论：我们的结果表明，由ATM抑制剂诱导的代谢变化是治疗HGSOC的潜在目标。我们证实，通过诱导衰老，在多种HGSOC细胞系中ATM抑制和非诺贝特联合治疗具有协同作用。结论：我们的结果表明，由ATM抑制剂诱导的代谢变化是治疗HGSOC的潜在目标。