Chen Chi-Wei, Buj Raquel, Dahl Erika S, Leon Kelly E, Aird Katherine M
Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA.
Heliyon. 2020 Sep 29;6(9):e05097. doi: 10.1016/j.heliyon.2020.e05097. eCollection 2020 Sep.
While therapies targeting deficiencies in the homologous recombination (HR) pathway are emerging as the standard treatment for high grade serous ovarian cancer (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. We found that the HR gene Ataxia Telangiectasia Mutated (ATM) is wildtype and its activity is upregulated in HGSOC compared to normal fallopian tube tissue. Interestingly, multiple pathways related to metabolism are inversely correlated with expression in HGSOC specimens, suggesting that combining ATM inhibition with metabolic drugs would be effective. Analysis of FDA-approved drugs from the Dependency Map demonstrated that ATM-low cells are more sensitive to fenofibrate, a PPARα agonist that affects multiple cellular metabolic pathways. Consistently, PPARα signaling is associated with expression. We validated that combined inhibition of ATM and treatment with fenofibrate is synergistic in multiple HGSOC cell lines by inducing senescence. Together, our results suggest that metabolic changes induced by ATM inhibitors are a potential target for the treatment of HGSOC.
虽然针对同源重组（HR）途径缺陷的疗法正在成为高级别浆液性卵巢癌（HGSOC）患者的标准治疗方法，但该策略仅限于约50%该途径存在缺陷的患者。因此，HR功能正常的肿瘤患者可能对这些疗法产生耐药性，需要 alternative strategies。我们发现，HR基因共济失调毛细血管扩张突变基因（ATM）是野生型的，与正常输卵管组织相比，其活性在HGSOC中上调。有趣的是，与代谢相关的多个途径与HGSOC标本中的表达呈负相关，这表明将ATM抑制与代谢药物联合使用可能有效。对来自依赖性图谱的FDA批准药物的分析表明，ATM低表达的细胞对非诺贝特更敏感，非诺贝特是一种影响多种细胞代谢途径的PPARα激动剂。一致地，PPARα信号与表达相关。我们通过诱导衰老验证了在多个HGSOC细胞系中，ATM抑制与非诺贝特治疗联合具有协同作用。总之，我们的结果表明，ATM抑制剂诱导的代谢变化是治疗HGSOC的一个潜在靶点。
