CHEK2 loss promotes prostate cancer resistance to PARP inhibitors

CHEK2 缺失促进前列腺癌对 PARP 抑制剂的耐药性

• 批准号: 10657806
• 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: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657806
• 关键词: Alleles; Androgen Receptor; BRCA mutations; BRCA1 gene; BRCA2 gene; Biological Assay; Biological Markers; CHEK2 gene; CRISPR screen; Cancer Patient; Cell Cycle Checkpoint; Cell Death; Cells; Cessation of life; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Damage; DNA Repair; DNA Sequence Alteration; DNA replication fork; Defect; Disease; Eligibility Determination; Enzymes; Event; FDA approved; Fiber; Future; Gene Mutation; Generations; Genes; Genetic; Genomics; Goals; Growth; In Vitro; Knock-out; Life; Malignant neoplasm of prostate; Measures; Mediating; Molecular Target; Mutate; Mutation; Pathway interactions; Patient Selection; Patients; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Proteins; Receptor Signaling; Research; Resistance; TP53 gene; Testing; Therapeutic; Tumor Suppressor Genes; United States; Up-Regulation; Validation; Work; abiraterone; advanced prostate cancer; androgen deprivation therapy; brca gene; cancer cell; castration resistant prostate cancer; clinical practice; clinically relevant; effective therapy; enzalutamide; gene panel; gene repair; genome-wide; homologous recombination; improved; in vivo; inhibitor; loss of function mutation; neoplastic cell; new therapeutic target; novel; personalized medicine; pre-clinical; predictive marker; prevent; prostate cancer cell; prostate cancer cell line; prostate cancer model; recombinational repair; repair function; response; targeted treatment; tumor

ABSTRACT Metastatic castration-resistant prostate cancer (mCRPC) is an incurable disease that is expected to account for approximately 33,000 deaths each year in the United States. Therapeutic options are limited for mCRPC 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 are among the most common genetic events and enriched in mCRPC. 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 (PARPis) are a new type of targeted therapy, which works by preventing the enzyme PARP from repairing damaged DNA in tumor cells. The BRCA1 and BRCA2 genes encode proteins essential for HR repair. Cancer cells lacking BRCA1/2 depend instead on PARP-regulated DNA repair and are highly sensitive to PARPis. The U.S. FDA has approved two PARP inhibitors (olaparib and rucaparib) for the treatment of mCRPC patients with deleterious BRCA1/2 or HR repair gene mutations. One of the major barriers to effective treatment using PARPis is how to select patients who most likely benefit from PARP inhibition. Resistance to PARPis also represents a formidable clinical problem. Through genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screens, we recently discovered a number of genes that mediate cellular response and resistance to PARP inhibition. Unexpectedly, we found that loss of CHEK2 (Checkpoint kinase 2), a cell cycle checkpoint regulator and tumor suppressor gene, significantly increased PCa cell resistance (instead of sensitivity) to PARP inhibition. CHEK2 plays a role in HR repair and CHEK2 alterations are currently used to predict olaparib response in the FDA-approved HR repair gene panel. The goal of this project is to determine to what extent loss of CHEK2 renders PCa cells resistant to PARP inhibition and define the underlying mechanisms in preclinical PCa models. At completion of this project, we expect to demonstrate that CHEK2 loss is a biomarker to predict PARPi resistance. The findings from this study may change patient eligibility for PARP inhibition and have a positive impact on future clinical practice.

抽象的 转移性castration-耐药前列腺癌（MCRPC）是一种无法治愈的疾病，有望 在美国，每年约有33,000人死亡。治疗选择有限 延长寿命的MCRPC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损伤反应是最常见的遗传事件之一，并富含MCRPC。 这些改变与前列腺癌（PCA）细胞中特定的治疗脆弱性有关。 具体而言，同源重组（HR）修复缺陷将预测对抑制多聚的敏感性 （ADP-核糖）聚合酶（PARP）。 PARP抑制剂（PARPIS）是一种新型的靶向疗法，可有效 通过防止酶PAR在肿瘤细胞中修复受损的DNA。 BRCA1和BRCA2基因 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Parpis高度敏感。美国FDA批准了两个PARP抑制剂（Olaparib和 rucaparib）用于治疗有害BRCA1/2或HR修复基因突变的MCRPC患者。 使用PARPI的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。对Parpis的抵抗力也代表了一个强大的临床问题。通过 全基因组CRISPR（群集定期间隔短的短质体重复序列）屏幕，我们最近 发现了许多介导细胞反应和对PARP抑制的抗性的基因。不料， 我们发现CHEK2的损失（检查点激酶2），细胞周期检查点调节剂和肿瘤抑制剂 基因，显着提高了PCA细胞耐药性（而不是敏感性）对PARP抑制。 CHEK2扮演角色 目前使用HR修复和CHEK2改变来预测FDA批准的HR中的Olaparib响应 修复基因面板。该项目的目的是确定CHEK2的损失在多大程度上呈现PCA细胞 抗PARP抑制和定义临床前PCA模型中的基本机制。完成时 这个项目，我们希望证明CHEK2损失是预测PARPI抗性的生物标志物。这 这项研究的结果可能会改变患者的PAR抑制资格，并对未来产生积极影响 临床实践。

项目成果

CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer.

• DOI: 10.1038/s41467-023-35880-y
• 发表时间: 2023-01-17
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Tsujino, Takuya;Takai, Tomoaki;Hinohara, Kunihiko;Gui, Fu;Tsutsumi, Takeshi;Bai, Xiao;Miao, Chenkui;Feng, Chao;Gui, Bin;Sztupinszki, Zsofia;Simoneau, Antoine;Xie, Ning;Fazli, Ladan;Dong, Xuesen;Azuma, Haruhito;Choudhury, Atish D. D.;Mouw, Kent W. W.;Szallasi, Zoltan;Zou, Lee;Kibel, Adam S. S.;Jia, Li
• 通讯作者: Jia, Li