Human cancers frequently harbour mutations in DNA repair genes, rendering the use of DNA damaging agents as an effective therapeutic intervention. As therapy-resistant cells often arise, it is important to better understand the molecular pathways that drive resistance in order to facilitate the eventual targeting of such processes. We employ recombination-defective diploid yeast as a model to demonstrate that, in response to genotoxic challenges, nearly all cells eventually undergo checkpoint adaptation, resulting in the generation of aneuploid cells with whole chromosome losses that have acquired resistance to the initial genotoxic challenge. We demonstrate that adaptation inhibition, either pharmacologically, or genetically, drastically reduces the occurrence of resistant cells. Additionally, the aneuploid phenotypes of the resistant cells can be specifically targeted to induce cytotoxicity. We provide evidence that TORC1 inhibition with rapamycin, in combination with DNA damaging agents, can prevent both checkpoint adaptation and the continued growth of aneuploid resistant cells.

人类癌症经常在DNA修复基因中带有突变，从而使DNA破坏剂成为有效的治疗手段。随着治疗耐药性细胞的频繁出现，重要的是更好地了解驱动耐药性的分子途径，以促进此类过程的最终靶向。我们采用重组缺陷型二倍体酵母作为模型来证明，响应遗传毒性挑战，几乎所有细胞最终都会经历检查点适应，从而导致具有完整染色体丢失的非整倍体细胞的产生，这些非整倍体细胞已获得了对初始遗传毒性挑战的抗性。我们证明，无论是从药理学还是基因上，适应性抑制都能大大减少耐药细胞的发生。另外，抗性细胞的非整倍性表型可以被特异性地靶向以诱导细胞毒性。我们提供的证据表明，雷帕霉素与DNA破坏剂联合使用可抑制TORC1的发生，既可以防止检查点适应，也可以防止非整倍体抗性细胞的持续生长。