PO.MCB05.02 · 分子与细胞生物学
抑制野生型IDH1诱导同源重组缺陷并增强胰腺癌对PARP抑制剂的敏感性
Wild-type IDH1 inhibition induces homologous recombination deficiency and enhances PARP inhibitor sensitivity in pancreatic cancer
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摘要 Abstract
中文摘要
目的：胰腺导管腺癌（PDAC）仍然是致死率最高的恶性肿瘤之一，治疗选择有限。虽然PARP抑制剂对具有同源重组缺陷（HRD）的肿瘤有益，但只有不到10-20%的PDAC病例携带此类突变。大多数为同源重组功能正常（HRP），代表着重大的未满足需求。在此，我们将野生型异柠檬酸脱氢酶1（wtIDH1）确定为HRP PDAC中HR修复的关键调控因子，并提出一种利用IDH1和PARP抑制来诱导合成致死的新型联合策略。
方法：我们利用HR和非同源末端连接（NHEJ）报告基因实验、Western blot以及染色质修饰分析评估了wtIDH1在DNA修复中的作用。通过细胞活力、凋亡和DNA损伤实验，在体外评估了IDH1抑制（ivosidenib）和PARP抑制（olaparib）单独及联合的作用。体内疗效在异种移植和原位PDAC小鼠模型中进行了检测，包括生存研究。此外，还分析了正在进行的Ib期临床试验（NCT05209074）中接受ivosidenib治疗的患者的肿瘤活检样本的HR通路活性和染色质改变。
结果：药理学抑制wtIDH1耗竭了alpha-酮戊二酸并诱导组蛋白过度甲基化，损害HR修复，并在HRP PDAC细胞系（MiaPaCa-2、Panc-1）中模拟出BRCA样表型。IDH1和PARP抑制剂联合协同增加了gamma-H2AX的积累和凋亡，降低了细胞活力。在体内，与单药治疗相比，双药治疗显著抑制了肿瘤生长并延长了生存期。重要的是，来自NCT05209074中接受ivosidenib治疗患者的肿瘤样本表现出HR修复蛋白表达降低，以及与BRCAness表型一致的表观遗传变化，支持了转化相关性。
结论：我们的研究发现揭示了wtIDH1在维持PDAC同源重组中的新作用。抑制wtIDH1在功能上诱导HRP肿瘤发生HR缺陷，使其对PARP抑制敏感。该联合策略为大多数缺乏经典HR突变的PDAC患者提供了一种有前景的治疗方法，值得进一步开展转化研发。
查看英文原文 English abstract
Objective : Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies with limited therapeutic options. While PARP inhibitors benefit tumors with homologous recombination deficiency (HRD), fewer than 10-20% of PDAC cases harbor such mutations. The majority are homologous recombination proficient (HRP), representing a significant unmet need. Here, we identify wild-type isocitrate dehydrogenase 1 (wtIDH1) as a critical regulator of HR repair in HRP PDAC and propose a novel combinatorial strategy using IDH1 and PARP inhibition to induce synthetic lethality.
Methods: We assessed the role of wtIDH1 in DNA repair using HR and non-homologous end joining (NHEJ) reporter assays, Western blotting, and chromatin modification analyses. Effects of IDH1 inhibition (ivosidenib) and PARP inhibition (olaparib), alone and combined, were evaluated in vitro through cell viability, apoptosis, and DNA damage assays. In vivo efficacy was tested in xenograft and orthotopic PDAC mouse models, including survival studies. Additionally, tumor biopsies from patients in the ongoing phase Ib clinical trial ( NCT05209074 ) receiving ivosidenib were analyzed for HR pathway activity and chromatin alterations.
Results: Pharmacologic wtIDH1 inhibition depleted alpha-ketoglutarate and induced histone hypermethylation, impairing HR repair and mimicking a BRCA-like phenotype in HRP PDAC cell lines (MiaPaCa-2, Panc-1). The combination of IDH1 and PARP inhibitors synergistically increased gamma-H2AX accumulation and apoptosis, reducing cell viability. In vivo, dual therapy significantly suppressed tumor growth and extended survival compared to monotherapies. Importantly, tumor samples from NCT05209074 patients treated with ivosidenib exhibited decreased expression of HR repair proteins and epigenetic changes consistent with a BRCAness phenotype, supporting translational relevance.
Conclusion: Our findings reveal a novel role for wtIDH1 in maintaining homologous recombination in PDAC. Inhibition of wtIDH1 functionally induces HR deficiency in HRP tumors, sensitizing them to PARP inhibition. This combination represents a promising therapeutic approach for the majority of PDAC patients lacking canonical HR mutations and warrants further translational development.
利益披露 Disclosure
M. Zarei, None..
O. Prajapati, None..
S. Abul-Khoudoud, None..
L. D. Rothermel, None..
R. Wang, None.