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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的转移性去势抵抗性前列腺癌（mCRPC）是一种无法治愈的疾病，预计美国每年约有 33,000 人死亡。治疗选择有限延长生命的 mCRPC 患者。迫切需要开发新型靶向疗法，特别是基于肿瘤基因组改变的个性化治疗。最近的基因组研究揭示了具有潜在基因组改变的各种可操作的分子靶标。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，并且在 mCRPC 中丰富。这些改变与前列腺癌（PCa）细胞的特定治疗脆弱性相关。具体来说，同源重组 (HR) 修复中的缺陷将预测对 Poly 抑制的敏感性。（ADP-核糖）聚合酶（PARP）。 PARP抑制剂（PARPis）是一种新型靶向治疗，其作用通过阻止 PARP 酶修复肿瘤细胞中受损的 DNA。 BRCA1 和 BRCA2 基因编码 HR 修复必需的蛋白质。缺乏 BRCA1/2 的癌细胞反而依赖 PARP 调节 DNA 修复并对 PARPis 高度敏感。美国FDA已批准两种PARP抑制剂（olaparib和 rucaparib）用于治疗具有有害 BRCA1/2 或 HR 修复基因突变的 mCRPC 患者。使用 PARPis 进行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 的耐药性也是一个棘手的临床问题。通过我们最近进行了全基因组 CRISPR（成簇规则间隔短回文重复序列）筛选发现了许多介导细胞反应和对 PARP 抑制的抵抗的基因。不料，我们发现细胞周期检查点调节剂和肿瘤抑制因子 CHEK2（检查点激酶 2）的缺失基因，显着增加 PCa 细胞对 PARP 抑制的抵抗力（而不是敏感性）。 CHEK2发挥作用 HR 修复和 CHEK2 改变目前用于预测 FDA 批准的 HR 中奥拉帕尼的反应修复基因面板。该项目的目标是确定 CHEK2 的缺失对 PCa 细胞造成何种程度的影响抵抗 PARP 抑制并确定临床前 PCa 模型的潜在机制。完成时在这个项目中，我们希望证明 CHEK2 丢失是预测 PARPi 耐药性的生物标志物。这这项研究的结果可能会改变患者接受 PARP 抑制的资格，并对未来产生积极影响临床实践。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

CRISPR 筛选揭示了前列腺癌中 PARP 抑制剂敏感性和耐药性的遗传决定因素。

DOI：
发表时间：
2023-01-17
期刊：
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;Mouw, Kent
通讯作者：
Mouw, Kent