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.

摘要

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