Targeting USP10 to regulate the DNA damage response in NSCLC

靶向 USP10 调节 NSCLC 中的 DNA 损伤反应

• 批准号: 10112548
• 负责人: GEROLD BEPLER
• 金额: $ 21.6万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-03 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112548
• 关键词: Apoptosis; Biological Markers; CHEK1 gene; Cancer Patient; Cell Cycle Checkpoint; Cells; Cisplatin; Conflict (Psychology); DNA Damage; DNA damage checkpoint; Data; Databases; Deubiquitinating Enzyme; Goals; Growth; HDAC6 gene; Lead; Literature; Malignant Neoplasms; Malignant neoplasm of lung; Messenger RNA; Mission; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Oncoproteins; Outcome; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacology; Platinum; Play; Proteins; Public Health; Renal Cell Carcinoma; Reporting; Research; Resistance; Role; Sampling; Subgroup; TP53 gene; Testing; The Cancer Genome Atlas; Time; Tumor Burden; Tumor Suppressor Proteins; Ubiquitin; Xenograft procedure; base; clinical development; clinically relevant; cohort; combat; improved; inhibitor/antagonist; knock-down; mutant; neoplastic cell; new therapeutic target; novel; patient derived xenograft model; response; therapeutic evaluation; tumor; ubiquitin-protein ligase

ABSTRACT Combating platinum resistance remains a daunting challenge in the treatment of lung cancer. Activation of the cellular DNA damage response (DDR) is an important determinant of cell sensitivity to cisplatin and other chemotherapeutic drugs, which eliminate tumor cells through induction of DNA damage and checkpoint activation. We have recently found that histone deacetylase 6 (HDAC6) may promote degradation of a key DDR protein, checkpoint kinase 1 (Chk1). The G2 cell cycle checkpoint is activated upon DNA damage in a Chk1- dependent mechanism, and prolonged G2 arrest could lead to apoptosis. We have also found that a deubiquitinating enzyme (DUB), ubiquitin-specific peptidase 10 (USP10), could stabilize HDAC6. Our group is the first to discover HDAC6's ubiquitin E3 ligase activity, but targeting HDAC6's E3 ligase activity pharmacologically is not currently possible. Therefore, we propose targeting USP10 to decrease the protein level of HDAC6, which in turn induces persistently high levels of Chk1 to activate a prolonged G2 checkpoint arrest upon cisplatin treatment, leading to apoptosis. Because the role of USP10 in cancer is context-dependent, we searched the TCGA databases and found that a high level of USP10 is associated with shorter overall survival (OS) in a subset of NSCLC with TP53 mutations from a cohort of ~1,000 NSCLC patients, indicating that USP10 may serve as an oncogene in this subset. Consistently, our preliminary data have shown that depletion of USP10 in TP53 mutant NSCLC xenografts drastically inhibits xenografts' growth and sensitizes them to cisplatin, indicating an oncogenic role for USP10 in this subgroup of NSCLC. Reports from other groups as well as ours have shown that HDAC6 stabilizes oncogenic mutant p53 (mutp53) and confers cisplatin resistance in NSCLC. Based on our preliminary data and the literature, we hypothesize that the USP10-HDAC6 axis down-regulates DNA damage response protein Chk1 to compromise the cell cycle checkpoint, leading to cisplatin resistance. Thus, targeting this axis would activate the checkpoint and destabilize oncogenic mutp53, which ultimately increases responsiveness to cisplatin and prolongs overall survival in NSCLC patients with TP53 mutations. To test this central hypothesis, we will first explore the mechanism by which the USP10-HDAC6 axis confers cisplatin resistance; we will then test the therapeutic potential of USP10 inhibition in treating TP53 mutant NSCLC and evaluate a correlation between USP10 expression and cisplatin response, as well as a correlation between expression of USP10's substrates and cisplatin response in a cohort of TP53 mutant NSCLC samples. The outcome of our proposal will establish the oncogenic role of USP10 in the mutp53 subset of NSCLC and provide a strong rationale for the development of clinically relevant USP10 inhibitors to treat this subset of NSCLC patients, thus improving cisplatin responses and overall survival.

抽象的 对抗铂耐药性仍然是肺癌治疗中的一项艰巨挑战。激活 细胞 DNA 损伤反应 (DDR) 的变化是细胞对顺铂和其他药物敏感性的重要决定因素 化疗药物，通过诱导 DNA 损伤和检查点消除肿瘤细胞 激活。我们最近发现组蛋白脱乙酰酶 6 (HDAC6) 可能促进关键 DDR 的降解 蛋白质、检查点激酶 1 (Chk1)。 G2 细胞周期检查点在 Chk1- 中的 DNA 损伤时被激活 依赖机制，延长 G2 停滞可能导致细胞凋亡。我们还发现一个 去泛素化酶 (DUB)、泛素特异性肽酶 10 (USP10) 可以稳定 HDAC6。我们组是 第一个发现HDAC6的泛素E3连接酶活性，但针对HDAC6的E3连接酶活性 目前从药理上来说是不可能的。因此，我们建议以 USP10 为目标来降低蛋白质水平 HDAC6，进而诱导持续高水平的 Chk1 激活长时间的 G2 检查点停滞 顺铂治疗后，导致细胞凋亡。因为 USP10 在癌症中的作用是依赖于背景的，我们 搜索TCGA数据库发现USP10水平高与总生存期短相关 (OS) 在约 1,000 名 NSCLC 患者队列中具有 TP53 突变的 NSCLC 子集中，表明 USP10 可能作为该子集中的癌基因。我们的初步数据一致表明，USP10 的消耗 在 TP53 突变 NSCLC 异种移植物中，显着抑制异种移植物的生长并使它们对顺铂敏感， 表明 USP10 在该 NSCLC 亚组中具有致癌作用。来自其他团体以及我们团体的报告 研究表明，HDAC6 可以稳定致癌突变体 p53 (mutp53)，并赋予 NSCLC 顺铂耐药性。 根据我们的初步数据和文献，我们假设 USP10-HDAC6 轴下调 DNA 损伤反应蛋白 Chk1 会损害细胞周期检查点，导致顺铂耐药。 因此，针对该轴将激活检查点并破坏致癌性 mutp53 的稳定性，最终 增加 TP53 突变 NSCLC 患者对顺铂的反应并延长总生存期。到 检验这个中心假设，我们将首先探讨 USP10-HDAC6 轴赋予 顺铂耐药；然后我们将测试 USP10 抑制在治疗 TP53 突变 NSCLC 中的治疗潜力 并评估 USP10 表达与顺铂反应之间的相关性，以及 一组 TP53 突变 NSCLC 样本中 USP10 底物的表达和顺铂反应。这 我们提案的结果将确定 USP10 在 NSCLC 的 mutp53 子集中的致癌作用，并提供 开发临床相关的 USP10 抑制剂来治疗这一 NSCLC 亚型的有力理由 患者，从而改善顺铂反应和总体生存率。