Targeting USP10 to regulate the DNA damage response in NSCLC

靶向 USP10 调节 NSCLC 中的 DNA 损伤反应

基本信息

  • 批准号:
    10311543
  • 负责人:
  • 金额:
    $ 17.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-12-03 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

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 对抗铂耐药性仍然是肺癌治疗中的一个艰巨挑战。激活 细胞DNA损伤反应(DDR)的水平是细胞对顺铂和其他化疗药物敏感性的重要决定因素。 化疗药物,通过诱导DNA损伤和检查点来消除肿瘤细胞 activation.我们最近发现组蛋白去乙酰化酶6(HDAC 6)可能会促进一个关键的DDR降解, 蛋白质,检查点激酶1(Chk 1)。G2细胞周期检查点在Chk 1- 依赖性机制,G2期阻滞延长可导致细胞凋亡。我们还发现, 去泛素化酶(DUB),泛素特异性肽酶10(USP 10),可以稳定HDAC 6。我们集团 第一个发现HDAC 6的泛素E3连接酶活性,但针对HDAC 6的E3连接酶活性 目前还不可能。因此,我们建议靶向USP 10以降低蛋白水平, HDAC 6,这反过来又诱导持续高水平的Chk 1激活延长的G2检查点阻滞 顺铂治疗后,导致细胞凋亡。由于USP 10在癌症中的作用是依赖于环境的,我们 检索了TCGA数据库,发现高水平的USP 10与较短的总生存期相关 (OS)在来自约1,000名非小细胞肺癌患者队列的具有TP 53突变的非小细胞肺癌子集中,表明USP 10 可能是这个亚群中的一个致癌基因。因此,我们的初步数据表明,USP 10的消耗 在TP 53突变的NSCLC异种移植物中, 表明USP 10在该NSCLC亚组中具有致癌作用。其他组织和我们的报告 已经显示HDAC 6稳定致癌突变体p53(mutp 53)并赋予NSCLC顺铂抗性。 基于我们的初步数据和文献,我们假设USP 10-HDAC 6轴下调了 DNA损伤反应蛋白Chk 1破坏细胞周期检查点,导致顺铂耐药。 因此,靶向该轴将激活检查点并使致癌mutp 53不稳定, 增加了TP 53突变NSCLC患者对顺铂的反应性,延长了总生存期。到 为了验证这一中心假设,我们将首先探索USP 10-HDAC 6轴赋予 顺铂耐药性;然后我们将测试USP 10抑制在治疗TP 53突变型NSCLC中的治疗潜力 并评估USP 10表达与顺铂反应之间的相关性,以及USP 10表达与顺铂反应之间的相关性。 TP 53突变NSCLC样本队列中USP 10底物的表达和顺铂反应。的 我们提案的结果将确定USP 10在NSCLC mutp 53亚群中的致癌作用,并提供 开发具有临床意义的USP 10抑制剂治疗该NSCLC子集的有力依据 患者,从而改善顺铂反应和总生存期。

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)
Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer.
  • DOI:
    10.1038/s41598-021-94019-5
  • 发表时间:
    2021-07-20
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Campeanu IJ;Jiang Y;Liu L;Pilecki M;Najor A;Cobani E;Manning M;Zhang XM;Yang ZQ
  • 通讯作者:
    Yang ZQ
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GEROLD BEPLER其他文献

GEROLD BEPLER的其他文献

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{{ truncateString('GEROLD BEPLER', 18)}}的其他基金

Developmental Research Program
发展研究计划
  • 批准号:
    10289607
  • 财政年份:
    2021
  • 资助金额:
    $ 17.64万
  • 项目类别:
Reducing Cancer Health Disparities in Detroit
减少底特律的癌症健康差异
  • 批准号:
    10289601
  • 财政年份:
    2021
  • 资助金额:
    $ 17.64万
  • 项目类别:
ETCTN Early Drug Development Opportunity Leadership program administrative supplement to Cancer Center Support Grant
ETCTN 早期药物开发机会领导计划对癌症中心支持补助金的行政补充
  • 批准号:
    10363981
  • 财政年份:
    2021
  • 资助金额:
    $ 17.64万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10684289
  • 财政年份:
    2021
  • 资助金额:
    $ 17.64万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10491131
  • 财政年份:
    2021
  • 资助金额:
    $ 17.64万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 17.64万
  • 项目类别:
Detroit Research on Cancer Survivors (Detroit ROCS)
底特律癌症幸存者研究(底特律 ROCS)
  • 批准号:
    10082435
  • 财政年份:
    2017
  • 资助金额:
    $ 17.64万
  • 项目类别:
Senior Leadership
高层领导
  • 批准号:
    8709336
  • 财政年份:
    2013
  • 资助金额:
    $ 17.64万
  • 项目类别:
Protocol Specific Research Support
协议特定研究支持
  • 批准号:
    8723966
  • 财政年份:
    2013
  • 资助金额:
    $ 17.64万
  • 项目类别:
Protocol Specific Research Support
协议特定研究支持
  • 批准号:
    8350790
  • 财政年份:
    2011
  • 资助金额:
    $ 17.64万
  • 项目类别:

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