The role of TRIM37 in driving tumorigenesis and cancer-specific vulnerability to PLK4 inhibition

TRIM37 在驱动肿瘤发生和癌症特异性对 PLK4 抑制的脆弱性中的作用

• 批准号: 10624789
• 负责人: Sergi Regot
• 金额: $ 49.78万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624789
• 关键词: 17q; 17q23; Automobile Driving; Biogenesis; Breast; Breast Cancer Cell; Cell Cycle Progression; Cell Proliferation; Cell division; Cells; Centrosome; Chemicals; Chromosome Segregation; Clinic; Clinical; Collaborations; Coupled; Data; Defect; Development; Down-Regulation; Exhibits; Failure; Functional disorder; Gene Amplification; Genes; Genetic; Genome; Genomic Instability; Genomics; Goals; Heterogeneity; Human; Hypersensitivity; Inherited; Malignant Neoplasms; Mammary Neoplasms; Mediating; Microtubule-Organizing Center; Microtubules; Mitotic; Mitotic spindle; Modeling; Molecular; Mutation; Neuroblastoma; Oncogenes; Oncogenic; Organelles; Organoids; PLK1 gene; PPM1D gene; Phosphoric Monoester Hydrolases; Phosphotransferases; Poly(ADP-ribose) Polymerase Inhibitor; Pre-Clinical Model; Primary Neoplasm; Proliferating; Property; Proteins; Reporting; Role; TP53 gene; Testing; Therapeutic; Tumor Promotion; Work; aurora B kinase; brca gene; cancer cell; cancer therapy; cell killing; effectiveness testing; genetic approach; genetic manipulation; imaging approach; inhibitor; loss of function mutation; malignant breast neoplasm; neoplastic cell; novel; novel therapeutics; overexpression; patient derived xenograft model; pharmacologic; preservation; protein expression; synthetic lethal interaction; tumor; tumorigenesis; ubiquitin ligase; ubiquitin-protein ligase

Project Summary The concept of synthetic lethality has been validated clinically with the use of PARP inhibitors in treating breast cancers with loss-of-function mutations in BRCA1/2. Nevertheless, only 5-10% of breast tumors are caused by inherited mutations in BRCA1/2, highlighting a need to identify new synthetic lethal interactions that can be exploited clinically. In this proposal, we capitalize on our recent discovery of a new synthetic lethal interaction that is exposed by a cancer-specific genetic alteration. Centrosomes are microtubule-organizing centers that catalyze the assembly of the mitotic spindle during cell division. Centrosome duplication is tightly coupled to cell cycle progression and controlled by the master regulatory kinase (Polo-like kinase 4) PLK4. Chemical inhibition of PLK4 activity leads to cell division in the absence of centrosome duplication, producing centrosome-less cells that exhibit delayed mitotic spindle assembly. Although most cancer cells can proliferate in the absence of centrosomes, we recently discovered that inhibition of PLK4 leads to centrosome depletion that selectively triggers mitotic catastrophe in cancer cells overexpressing TRIM37. This has therapeutic relevance as the TRIM37 chromosomal locus is amplified in 50- 60% of neuroblastomas and ~10% of breast cancers. In addition, amplification of this region is associated with aggressive cancers with highly rearranged and unstable genomes. In this application, we will define how TRIM37 overexpression promotes tumorigenesis and increases the vulnerability to PLK4 inhibitors. We will also test the effectiveness of PLK4 inhibition in achieving selective killing of human cancer organoids with TRIM37 amplification. Aim 1 will determine how TRIM37 overexpression increases the sensitivity to PLK4 inhibitors and test if TRIM37-driven centrosome dysfunction contributes to tumorigenesis by promoting mitotic errors. The 17q23 amplicon contains ~30 genes, including TRIM37 and the TP53-antagonizing phosphatase PPM1D. The oncogenic properties of PPM1D overexpression have been validated in several models. Selective PPM1D inhibitors have been developed, but how PPM1D cooperates with other genes encoded in the 17q23 amplicon remains unknown. In Aim 2, we determine if PPM1D overexpression promotes TRIM37-mediated genomic instability and test if PPM1D inhibition can potentiate the action of PLK4 inhibitors in these tumors. Finally, Aim 3 will examine if TRIM37 overexpression confers increased sensitivity to PLK4 inhibition in breast and neuroblastoma tumor organoids. Understanding the role of TRIM37 in tumorigenesis will help define how its overexpression drives the development of aggressive cancers and provide a rationale for the use of PLK4i in the treatment of cancers with genomic amplification of TRIM37.

项目摘要 合成致命性的概念已经通过使用PARP抑制剂在临床上得到验证 具有BRCA1/2功能缺失突变的乳腺癌。然而，只有5%-10%的乳腺癌是 由BRCA1/2的遗传突变引起，突显出需要识别新的合成致死相互作用 可以在临床上利用。在这项提议中，我们利用了我们最近发现的一种新的合成致命物质 通过癌症特有的基因改变暴露出来的相互作用。 中心体是微管组织中心，在细胞过程中催化有丝分裂纺锤体的组装 组织。中心体复制与细胞周期进程紧密相连，并受主控器控制 调节蛋白激酶(Polo-like kinase4)Plk4。化学抑制Plk4活性导致细胞分裂 没有中心体复制，产生无中心体的细胞，表现出延迟的有丝分裂纺锤体 集合。虽然大多数癌细胞在没有中心体的情况下都能增殖，但我们最近发现 Plk4的抑制会导致中心体耗尽，从而选择性地触发癌细胞的有丝分裂灾难 过度表达TRIM37。这具有治疗意义，因为TRIM37染色体上的基因座在50%- 60%的神经母细胞瘤和约10%的乳腺癌。此外，该区域的扩增与 具有高度重排和不稳定基因组的侵袭性癌症。在本应用程序中，我们将定义 TRIM37过表达促进肿瘤发生，增加对Plk4抑制剂的易感性。我们会 还测试了Plk4抑制对人类癌症有机物的选择性杀伤效果 用TRIM37扩增。 AIM 1将确定TRIM37过表达如何增加对Plk4抑制剂的敏感性，并测试是否 TRIM37驱动的中心体功能障碍通过促进有丝分裂错误而促进肿瘤的发生。17q23 扩增子包含约30个基因，包括TRIM37和TP53-拮抗磷酸酶PPM1D。这个 PPM1D过度表达的致癌特性已在几个模型中得到验证。选择性PPM1D 已经开发出了抑制剂，但PPM1D如何与17q23扩增子中编码的其他基因合作 仍然不为人知。在目标2中，我们确定PPM1D的过度表达是否促进了TRIM37介导的基因组 不稳定和测试PPM1D抑制是否可以加强Plk4抑制剂在这些肿瘤中的作用。最后，瞄准 3将研究TRIM37的过度表达是否会增加乳房和乳房对Plk4抑制的敏感性 神经母细胞瘤，肿瘤细胞器。了解TRIM37在肿瘤发生中的作用将有助于确定它是如何 过度表达推动侵袭性癌症的发展，并为PLK4i的使用提供了理论基础 利用基因组扩增TRIM37基因治疗癌症。