PURPOSE Emergence of mismatch repair (MMR) deficiency is a frequent mechanism of acquired resistance to the alkylating chemotherapeutic temozolomide (TMZ) in gliomas. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been shown to potentiate TMZ cytotoxicity in several cancer types, including gliomas. We tested whether PARP inhibition could re-sensitize MSH6-null MMR-deficient gliomas to TMZ, and assessed the role of the base excision repair (BER) DNA damage repair pathway in PARPi-mediated effects. EXPERIMENTAL DESIGN Isogenic pairs of MSH6 wild-type and MSH6-inactivated human glioblastoma (GBM) cells (including both IDH1/2 wild-type and IDH1 mutant), as well as MSH6-null cells derived from a patient with recurrent GBM were treated with TMZ, the PARPi veliparib or olaparib, and combination thereof. Efficacy of PARPi combined with TMZ was assessed in vivo. We used genetic and pharmacological approaches to dissect the contribution of BER. RESULTS While having no detectable effect in MSH6 wild-type GBMs, PARPi selectively restored TMZ sensitivity in MSH6-deficient GBM cells. This genotype-specific restoration of activity translated in vivo, where combination treatment of veliparib and TMZ showed potent suppression of tumor growth of MSH6-inactivated orthotopic xenografts, compared with TMZ monotherapy. Unlike PARPi, genetic and pharmacological blockage of BER pathway did not re-sensitize MSH6-inactivated GBM cells to TMZ. Similarly, CRISPR PARP1 knockout did not re-sensitize MSH6-inactivated GBM cells to TMZ. CONCLUSIONS PARPi restoration of TMZ chemosensitivity in MSH6-inactivated glioma represents a promising strategy to overcome acquired chemoresistance caused by MMR deficiency. Mechanistically, this PARPi-mediated synthetic phenotype was independent of BER blockage and was not recapitulated by loss of PARP1.

中文翻译：

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失配修复缺陷胶质母细胞瘤中PARP抑制剂对替莫唑胺敏感性的恢复独立于碱基切除修复。

目的错配修复（MMR）缺乏症的出现是神经胶质瘤中对烷基化替莫唑胺（TMZ）产生耐药性的常见机制。聚（ADP-核糖）聚合酶抑制剂（PARPi）已显示出可增强包括胶质瘤在内的几种癌症的TMZ细胞毒性。我们测试了PARP抑制作用是否可以使TMH无效的MSH6空MMR缺陷神经胶质瘤重新敏感，并评估了碱基切除修复（BER）DNA损伤修复途径在PARPi介导的作用中的作用。实验设计用MSH6野生型和MSH6灭活的人胶质母细胞瘤（GBM）细胞（包括IDH1 / 2野生型和IDH1突变体）以及来源于患有复发性GBM的患者的MSH6 null细胞等基因对进行治疗TMZ，PARPi veliparib或olaparib及其组合。在体内评估了PARPi与TMZ联合的功效。我们使用遗传和药理学方法来分析BER的贡献。结果尽管在MSH6野生型GBM中没有可检测的作用，但PARPi在MSH6缺陷型GBM细胞中选择性恢复了TMZ敏感性。这种基因型特异性的活性恢复体内翻译，与TMZ单一疗法相比，维利帕利布和TMZ的联合治疗显示出MSH6灭活的原位异种移植物对肿瘤生长的有效抑制。与PARPi不同，BER途径的遗传和药理学阻断作用不会使MSH6灭活的GBM细胞对TMZ重新敏感。同样，CRISPR PARP1敲除并未使MSH6灭活的GBM细胞对TMZ重新敏感。结论在MSH6灭活的神经胶质瘤中PARPi恢复TMZ的化学敏感性代表了克服由MMR缺乏引起的获得性化学耐药性的有前途的策略。从机理上讲，这种PARPi介导的合成表型与BER阻滞无关，并且不会因PARP1的丢失而概括。