RNASEH2B loss to predict response to PARP inhibitor in prostate cancer

RNASEH2B 缺失可预测前列腺癌对 PARP 抑制剂的反应

• 批准号: 10403681
• 负责人: Li Jia
• 金额: $ 20.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-10 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403681
• 关键词: 13q14; Affect; Androgen Antagonists; Androgen Receptor; BRCA mutations; BRCA1 gene; BRCA2 gene; Biological Assay; CRISPR screen; CRISPR/Cas technology; Cancer Patient; Cell Death; Cell Lineage; Cell model; Cessation of life; Chromatin; Chromosomes; Clinical; Clinical Trials; DNA Damage; DNA Repair; DNA Sequence Alteration; DNA biosynthesis; Data Set; Defect; Disease; Disease remission; Enzymes; Event; Excision Repair; Future; Generations; Genes; Genetic; Genetic Engineering; Genomics; Goals; Human; Hypersensitivity; In Vitro; Knock-out; Knockout Mice; Lead; Lesion; Life; Malignant neoplasm of prostate; Measures; Mediating; Molecular Target; Mouse Cell Line; Mutate; Mutation; Patients; Play; Poly(ADP-ribose) Polymerases; Proteins; RB1 gene; Research; Resistance; Ribonucleases; Ribonucleotides; Role; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; United States; Work; abiraterone; advanced prostate cancer; androgen deprivation therapy; base; brca gene; cancer cell; castration resistant prostate cancer; effective therapy; enzalutamide; gene discovery; genome-wide; homologous recombination; improved; in vivo; inhibitor; men; mouse model; neoplastic cell; new therapeutic target; novel; personalized medicine; potential biomarker; pre-clinical; predicting response; prevent; prostate cancer cell; prostate cancer cell line; prostate cancer model; recombinational repair; resistance mechanism; response; targeted treatment; tumor

ABSTRACT Metastatic castration-resistant prostate cancer (CRPC) is an incurable disease that is expected to account for ~ 31,000 deaths each year in the United States. There are limited therapeutic options for metastatic CRPC patients that extend life. There is an urgent need for developing novel targeted therapies, especially personalized therapies based on genomic alterations in tumors. Recent genomic studies have revealed a variety of actionable molecular targets with underlying genomic alterations. Notably, alterations in genes involved in DNA damage response (DDR) are among the most common genetic events and enriched in metastatic CRPC. These alterations have been correlated with particular therapeutic vulnerabilities in prostate cancer (PCa) cells. Specifically, defects in homologous recombination (HR) repair would predict sensitivity to inhibition of Poly (ADP-ribose) polymerase (PARP). PARP inhibitors (PARPi) are a new type of targeted therapy, which works by preventing the enzyme PARP from repairing damaged DNA in tumor cells. BRCA1/2 encode proteins essential for HR repair. Cancer cells lacking BRCA1/2 depend instead on PARP-regulated DNA repair and are hypersensitive to PARPi. The U.S. FDA has approved two PARP inhibitors (olaparib and rucaparib) for treatment of metastatic CRPC patients with HR repair mutations (or deleterious BRCA mutations) based on the results from recent clinical trials. One of the major barriers to effective treatment using PARPi is how to select patients who most likely benefit from PARP inhibition. BRCA mutations can predict PARPi response with 50-60% accuracy. However, the degree to which patients with non-BCRA genomic alterations respond to PARPi remains unclear. Through a genome-wide CRISPR screen, we have recently discovered that loss of RNASEH2B in PCa cells may predict response to PARP inhibition. RNASEH2B is one of the three RNase H2 subunits that are thought to play a role in DNA replication. A recent study has demonstrated its function in ribonucleotide excision repair, which may contribute to PARP-trapping lesions. Importantly, analysis of TCGA datasets revealed RNASEH2B deep deletions in 17% of PCa tumors. Co-deletion of RNASEH2B and RB1 on chromosome13q14 frequently occurs. In addition, the results from our CRISPR screening further suggest that loss of TP53 may render PCa cells resistance to PARPi. Therefore, the goal of this project is to determine (1) to what extent loss of RNASEH2B confers a cellular response to PARPi in preclinical PCa models; (2) to what extent inactivation of TP53 and RB1 influences the response to PARPi. The successful implementation of this project will set the stage for future clinical trials in PCa patients with RNASEH2B/TP53/RB1 alterations and significantly expand the pool of eligible patients for PARP inhibition.

抽象的 转移性castration-耐药前列腺癌（CRPC）是一种无法治愈的疾病，预计将考虑 在美国，每年约有31,000人死亡。转移性CRPC的治疗选择有限 延长寿命的患者。迫切需要开发新颖的目标疗法，尤其是 基于肿瘤基因组改变的个性化疗法。最近的基因组研究表明 具有潜在基因组改变的各种可作用的分子靶标。值得注意的是，基因的改变 参与DNA损伤反应（DDR）是最常见的遗传事件之一，并丰富了 转移性CRPC。这些变化与前列腺中特定的治疗脆弱性有关 癌症（PCA）细胞。具体而言，同源重组（HR）修复缺陷将预测对 抑制聚（ADP-核糖）聚合酶（PARP）。 PARP抑制剂（PARPI）是一种新型的目标 治疗方法是防止酶PARP修复肿瘤细胞中受损受损的DNA的治疗。 BRCA1/2 编码蛋白质对人力资源维修必不可少的蛋白质。缺乏BRCA1/2的癌细胞取决于PARP调节 DNA修复，对PARPI高度敏感。美国FDA批准了两个PARP抑制剂（Olaparib和 rucaparib）用于治疗HR修复突变（或有害BRCA）转移性CRPC患者 突变）基于最近的临床试验的结果。 使用PARPI有效治疗的主要障碍之一是如何选择最有可能的患者 受益于PARP抑制。 BRCA突变可以以50-60％的精度预测PARPI响应。然而， 非BCRA基因组改变对PARPI的响应程度尚不清楚。通过 一个全基因组CRISPR屏幕，我们最近发现PCA细胞中RNaseH2b的损失可能 预测对PARP抑制的反应。 rnaseh2b是被认为是的三个RNase H2亚基之一 在DNA复制中起作用。最近的一项研究表明，它在核糖核苷酸切除修复中的功能， 这可能会导致PARP诱饵病变。重要的是，对TCGA数据集的分析显示RNASEH2B 17％的PCA肿瘤中的深层删除。 RNASEH2B和RB1在Chromosome13Q14上的共同删除经常 发生。此外，我们的CRISPR筛查的结果进一步表明，TP53的损失可能会导致PCA 细胞对PARPI的抗性。因此，该项目的目的是确定（1） RNASEH2B赋予临床前PCA模型中对PARPI的细胞反应； （2）在多大程度上失活 TP53和RB1影响对PARPI的反应。该项目的成功实施将设置 RNASEH2B/TP53/RB1改变的PCA患者未来临床试验的阶段，并显着扩展 合格患者的PARP抑制作用。

项目成果

RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer.

• DOI: 10.1126/sciadv.abl9794
• 发表时间: 2022-02-18
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Miao C;Tsujino T;Takai T;Gui F;Tsutsumi T;Sztupinszki Z;Wang Z;Azuma H;Szallasi Z;Mouw KW;Zou L;Kibel AS;Jia L
• 通讯作者: Jia L