Institut Curie, PSL Research University, CNRS, INSERM, UMR 3347, F-91405, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS, INSERM, UMR 3347, F-91405 Orsay, France; Onxeo, F-75015, Paris, France.
Institut Curie, PSL Research University, CNRS, INSERM, UMR 3347, F-91405, Orsay, France; Université Paris-Sud, Université Paris-Saclay, CNRS, INSERM, UMR 3347, F-91405 Orsay, France.
Neoplasia. 2019 Sep;21(9):863-871. doi: 10.1016/j.neo.2019.06.006. Epub 2019 Jul 27.
The Achilles heel of anticancer treatments is intrinsic or acquired resistance. Among many targeted therapies, the DNA repair inhibitors show limited efficacy due to rapid emergence of resistance. We examined evolution of cancer cells and tumors treated with AsiDNA, a new DNA repair inhibitor targeting all DNA break repair pathways. Effects of AsiDNA or Olaparib were analyzed in various cell lines. Frequency of AsiDNA- and olaparib-resistant clones was measured after 2 weeks of continuous treatment in KBM7 haploid cells. Cell survivals were also measured after one to six cycles of 1-week treatment and 1-week recovery in MDA-MB-231 and NCI-H446. Transcriptomes of cell populations recovering from cyclic treatments or mock treatment were compared. MDA-MB-231 xenografted models were treated with three cycles of AsiDNA to monitor the effects of treatment on tumor growth and transcriptional modifications. No resistant clones were selected after AsiDNA treatment (frequency < 3x10) in treatment conditions that generate resistance to olaparib at a frequency of 7.2x10 resistant clones per treated cell. Cyclic treatments promote cumulative sensitivity characterized by a higher mortality of cells having undergone previous treatment cycles. This sensitization was stable, and transcriptome analysis revealed a major gene downregulation with a specific overrepresentation of genes coding for targets of DNA-PK. Such changes were also detected in tumor models which showed impaired growth after cycles of AsiDNA treatment.
癌症治疗的阿喀琉斯之踵是内在或获得性耐药。在许多靶向治疗中，由于耐药性的迅速出现，DNA 修复抑制剂的疗效有限。我们研究了用 AsiDNA（一种针对所有 DNA 断裂修复途径的新型 DNA 修复抑制剂）治疗的癌细胞和肿瘤的进化。在各种细胞系中分析了 AsiDNA 或奥拉帕利的作用。在 KBM7 单倍体细胞中连续治疗 2 周后，测量 AsiDNA 和奥拉帕利耐药克隆的频率。还在 MDA-MB-231 和 NCI-H446 中测量了经过 1 周治疗和 1 周恢复后的 1 至 6 个周期后的细胞存活率。比较了从周期性治疗或模拟治疗中恢复的细胞群体的转录组。用 AsiDNA 治疗 MDA-MB-231 异种移植模型，以监测治疗对肿瘤生长和转录修饰的影响。在产生对奥拉帕利耐药频率为 7.2x10 个耐药克隆/处理细胞的治疗条件下，AsiDNA 处理后未选择耐药克隆（频率 <3x10）。周期性治疗促进累积敏感性，表现为先前治疗周期的细胞死亡率更高。这种敏化作用是稳定的，转录组分析显示基因下调主要与编码 DNA-PK 靶标的基因的特异性过表达有关。在肿瘤模型中也检测到了这种变化，这些模型在 AsiDNA 治疗周期后显示出生长受损。
