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.

摘要