El Touny Lara H, Hose Curtis, Connelly John, Harris Erik, Monks Anne, Dull Angie B, Wilsker Deborah F, Hollingshead Melinda G, Gottholm-Ahalt Michelle, Alcoser Sergio Y, Mullendore Michael E, Parchment Ralph E, Doroshow James H, Teicher Beverly A, Rapisarda Annamaria
Molecular Pharmacology Laboratory, Leidos Biomedical Research Inc., FNLCR, Frederick, MD, USA.
Current address: Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, NIH, Bethesda, MD, USA.
Oncotarget. 2021 Oct 12;12(21):2114-2130. doi: 10.18632/oncotarget.28090.
The therapeutic efficacy of temozolomide (TMZ) is hindered by inherent and acquired resistance. Biomarkers such as MGMT expression and MMR proficiency are used as predictors of response. However, not all MGMT/MMR patients benefit from TMZ treatment, indicating a need for additional patient selection criteria. We explored the role of ATR in mediating TMZ resistance and whether ATR inhibitors (ATRi) could reverse this resistance in multiple cancer lines. We observed that only 31% of MGMT/MMR patient-derived and established cancer lines are sensitive to TMZ at clinically relevant concentrations. TMZ treatment resulted in DNA damage signaling in both sensitive and resistant lines, but prolonged G/M arrest and cell death were exclusive to sensitive models. Inhibition of ATR but not ATM, sensitized the majority of resistant models to TMZ and resulted in measurable DNA damage and persistent growth inhibition. Also, compromised homologous recombination (HR) via RAD51 or BRCA1 loss only conferred sensitivity to TMZ when combined with an ATRi. Furthermore, low REV3L mRNA expression correlated with sensitivity to the TMZ and ATRi combination and . This suggests that HR defects and low REV3L levels could be useful selection criteria for enhanced clinical efficacy of an ATRi plus TMZ combination.
替莫唑胺（TMZ）的治疗效果受到固有耐药性和获得性耐药性的阻碍。诸如MGMT表达和错配修复（MMR）功能等生物标志物被用作反应的预测指标。然而，并非所有MGMT/MMR患者都能从TMZ治疗中获益，这表明需要额外的患者选择标准。我们探讨了共济失调毛细血管扩张症和Rad3相关蛋白（ATR）在介导TMZ耐药性中的作用，以及ATR抑制剂（ATRi）是否能在多种癌细胞系中逆转这种耐药性。我们观察到，在临床相关浓度下，只有31%的源自MGMT/MMR患者的已建立癌细胞系对TMZ敏感。TMZ治疗在敏感和耐药细胞系中均导致DNA损伤信号传导，但延长的G/M期阻滞和细胞死亡仅在敏感模型中出现。抑制ATR而非共济失调毛细血管扩张突变基因（ATM），可使大多数耐药模型对TMZ敏感，并导致可测量的DNA损伤和持续的生长抑制。此外，仅当与ATRi联合使用时，通过RAD51或乳腺癌1号基因（BRCA1）缺失导致的同源重组（HR）受损才赋予对TMZ的敏感性。此外，低REV3L信使核糖核酸（mRNA）表达与对TMZ和ATRi联合治疗的敏感性相关。这表明HR缺陷和低REV3L水平可能是提高ATRi加TMZ联合治疗临床疗效的有用选择标准。
