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 < 3x10⁻⁸) in treatment conditions that generate resistance to olaparib at a frequency of 7.2x10⁻⁷ 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.

抗癌治疗的致命弱点是内在或获得性耐药。在许多靶向疗法中，由于抗药性的快速出现，DNA修复抑制剂显示出有限的功效。我们检查了用AsiDNA处理的癌细胞和肿瘤的进化，AsiDNA是一种靶向所有DNA断裂修复途径的新型DNA修复抑制剂。在各种细胞系中分析了AsiDNA或Olaparib的作用。在KBM7单倍体细胞中连续治疗2周后，测量抗AsiDNA和olaparib的克隆的频率。在MDA-MB-231和NCI-H446中进行1至6个疗程的1周治疗和1周恢复后，还测量了细胞存活率。比较了从循环处理或模拟处理中恢复的细胞群体的转录组。用三个周期的AsiDNA处理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。AsiDNA处理后未选择抗性克隆（频率<3x10^-8）在每个条件下产生对olaparib产生抗药性的治疗条件下，频率为7.2x10 ^-7个抗药性克隆。循环处理促进累积敏感性，其特征在于经历先前处理循环的细胞具有更高的死亡率。这种敏化作用是稳定的，转录组分析揭示了主要的基因下调，其中特定过量的编码DNA-PK靶标的基因被过度表达。在肿瘤模型中也检测到这种变化，该肿瘤模型在AsiDNA治疗周期后显示出受损的生长。