文章：

甲基他汀通过靶向组蛋白去甲基化酶JMJD1B/C增强卵巢癌细胞对PARP抑制的敏感性

Methylstat sensitizes ovarian cancer cells to PARP-inhibition by targeting the histone demethylases JMJD1B/C 

原文发布日期：2025-02-06 

英文摘要：

PARP-inhibitors (PARPi) are an integral part of ovarian cancer treatment. However, overcoming acquired PARPi resistance or increasing the benefit of PARPi in patients without homologous recombination deficiency (HRD) remains an unmet clinical need. We sought to identify genetic modulators of PARPi response, guiding pharmacological PARPi sensitization. CRISPR-Cas9 mediated loss-of-function screen with a focused sgRNA library revealed that DNA-demethylases JMJD1B/JMJD1C, targetable by the small inhibitor methylstat, promote PARPi resistance. Methylstat synergistically interacted with olaparib, and (re-)sensitized ovarian cancer cells to PARPi treatment, surpassing the efficacy of common demethylase inhibitors. Genetic knockout of JMJD1B and/or JMJD1C phenocopied the effect of methylstat in an additive manner. Validation studies revealed methylstat to be a universal PARPi-sensitizing drug, effective, regardless of PARPi resistance status or BRCA1 mutational background. Methylstat modulated clonal cancer dynamics by mitigating positive selection of PARPi-resistant or BRCA1-proficient cells under olaparib treatment. Using a model of PARPi-induced cellular toxicity, we showed that methylstat impairs cellular DNA repair, indicated by an increased susceptibility of ovarian cancer cells to olaparib-induced DNA double strand breaks after methylstat exposure. This study proposes the histone demethylase inhibitor methylstat as an epigenetic drug for overcoming PARPi-resistance or for increasing efficacy of PARPi beyond HRD in ovarian cancer patients. 

摘要翻译： 

PARP抑制剂（PARPi）是卵巢癌治疗的重要组成部分。然而，克服获得性PARPi耐药性或增强同源重组缺陷（HRD）阴性患者对PARPi的治疗获益仍是未满足的临床需求。我们通过CRISPR-Cas9介导的功能缺失筛选与特异性sgRNA文库，发现DNA去甲基化酶JMJD1B/JMJD1C（可被小分子抑制剂methylstat靶向）会促进PARPi耐药。Methylstat与奥拉帕尼产生协同作用，使卵巢癌细胞（重新）对PARPi治疗敏感，其疗效优于常见去甲基化酶抑制剂。JMJD1B和/或JMJD1C的基因敲除以叠加方式复现了methylstat的效应。验证研究显示methylstat是一种普适性PARPi增敏剂，其有效性不受PARPi耐药状态或BRCA1突变背景的影响。通过调控克隆性癌症动态，methylstat可减弱奥拉帕尼治疗条件下PARPi耐药或BRCA1正常细胞的阳性选择。在PARPi诱导细胞毒性模型中，methylstat通过增加卵巢癌细胞对奥拉帕尼诱导DNA双链断裂的敏感性，表明其可损害细胞DNA修复功能。本研究提出组蛋白去甲基化酶抑制剂methylstat作为一种表观遗传药物，可用于克服PARPi耐药或提高PARPi在HRD阴性卵巢癌患者中的疗效。

原文链接：

Methylstat sensitizes ovarian cancer cells to PARP-inhibition by targeting the histone demethylases JMJD1B/C