PDF(Pubmed)
Abstract：
The tumor-suppressor p53 is commonly inactivated in colorectal cancer and pancreatic ductal adenocarcinoma, but existing treatment options for p53-mutant (p53Mut) cancer are largely ineffective. Here, we report a therapeutic strategy for p53Mut tumors based on abnormalities in the DNA repair response. Investigation of DNA repair upon challenge with thymidine analogs reveals a dysregulation in DNA repair response in p53Mut cells that leads to accumulation of DNA breaks. Thymidine analogs do not interrupt DNA synthesis but induce DNA repair that involves a p53-dependent checkpoint. Inhibitors of poly(ADP-ribose) polymerase (PARPis) markedly enhance DNA double-strand breaks and cell death induced by thymidine analogs in p53Mut cells, whereas p53 wild-type cells respond with p53-dependent inhibition of the cell cycle. Combinations of trifluorothymidine and PARPi agents demonstrate superior anti-neoplastic activity in p53Mut cancer models. These findings support a two-drug combination strategy to improve outcomes for patients with p53Mut cancer.
摘要：
肿瘤抑制因子p53在结直肠癌和胰腺导管腺癌中通常失活，但是现有的p53突变（p53Mut）癌症的治疗方案在很大程度上是无效的。这里,我们报道了基于DNA修复反应异常的p53Mut肿瘤的治疗策略.在用胸苷类似物攻击时DNA修复的研究揭示了p53Mut细胞中DNA修复反应的失调,其导致DNA断裂的积累。胸苷类似物不中断DNA合成,但诱导涉及p53依赖性检查点的DNA修复。聚（ADP-核糖）聚合酶（PARPis）的抑制剂显着增强p53Mut细胞中胸苷类似物诱导的DNA双链断裂和细胞死亡，而p53野生型细胞对细胞周期的p53依赖性抑制作用。三氟胸苷和PARPi药物的组合在p53Mut癌症模型中表现出优异的抗肿瘤活性。这些发现支持两种药物联合策略来改善p53Mut癌症患者的预后。
