Preventing adaptive drug resistance through Mediator kinase inhibition

通过抑制介体激酶来预防适应性耐药性

基本信息

项目摘要

Cancer drug resistance is driven in part by the plasticity of tumor cells that allows for therapy-induced adaptation of their transcriptional program. This adaptive drug resistance is associated with the acquisition of various phenotypic changes that promote tumor growth, metastasis and resistance to other therapies. Experimental drugs targeting CDK8/19 Mediator kinase that regulates transcriptional reprogramming were found to suppress the development of resistance to different classes of targeted and conventional anticancer agents. We hypothesize that the emergence of adaptive drug resistance in vitro and in vivo, with concurrent acquisition of tumor-promoting phenotypes, can be prevented by inhibiting Mediator kinase. We will test this hypothesis in HER2-positive breast cancers by analyzing the effects of Mediator kinase inhibition on the emergence of resistance to a HER2-targeting drug (lapatinib) and a conventional drug (paclitaxel). We will pursue the following Specific Aims. (1) The effect of Mediator kinase deficiency on the development of adaptive drug resistance in vitro will be analyzed by generating derivatives of HER2-positive human breast cancer cell lines that will express wild-type or kinase-dead Mediator kinase and by analyzing the effects of Mediator kinase mutagenesis or treatment with selective CDK8/19 inhibitors on the emergence of adaptive resistance to lapatinib or paclitaxel. Comprehensive phenotypic, genomic and transcriptomic analyses will be used to evaluate the effect of drug adaptation and Mediator kinase inhibition on the acquisition of tumor-promoting phenotypes and to identify signal transduction pathways, inhibitors of which could be combined with CDK8/19 inhibitors to enhance the prevention of resistance. (2) HER2-positive human cell lines with different Mediator kinase status and a panel of HER2- positive breast cancer patient-derived xenografts (PDX) will be selected for lapatinib and paclitaxel resistance in vivo, to compare the resistance-preventing effects of Mediator kinase deficiency in tumor cells alone and with the effects of its pharmacological inhibition in both tumor and stromal cells. Transcriptomic and phenotypic analysis will be used to delineate the effects of drug selection and Mediator kinase inhibition on gene expression in tumor and stromal cells. Whole exome sequencing of PDX tumors will reveal if Mediator kinase inhibition prevents the emergence of new drug-resistant tumor lineages or suppresses the growth of drug-resistant cells that may pre-exist in heterogeneous PDXs. (3) The effects of Mediator kinase on the emergence of drug resistance will also be investigated in a murine Her2/Neu-driven mouse mammary carcinoma cells adapted for syngeneic growth, both in vitro (as in Aim 1) and in vivo using both immunocompetent and immunodeficient hosts. This analysis will elucidate the effect of the host immune system on drug adaptation and the role of Mediator kinase in this effect. The proposed program will delineate the roles of Mediator kinase in tumor adaptation to treatment, in vitro and in vivo, and will indicate whether Mediator kinase-inhibiting drugs may be able to extend the duration of remission induced by cancer therapy.
癌症耐药性部分由肿瘤细胞的可塑性驱动,这种可塑性允许治疗诱导的适应 他们的转录程序。这种适应性耐药性与获得各种 表型改变促进肿瘤生长、转移和对其他疗法的抗性。实验 靶向调节转录重编程的CDK 8/19介导激酶的药物被发现抑制 对不同类别的靶向和常规抗癌剂产生耐药性。我们 假设体外和体内适应性耐药的出现,同时获得 肿瘤促进表型,可以通过抑制介体激酶来预防。我们将测试这个假设, 通过分析中介激酶抑制对HER 2阳性乳腺癌的出现的影响, 对HER 2靶向药物(拉帕替尼)和常规药物(紫杉醇)的耐药性。我们将继续努力 具体目标。(1)介导激酶缺陷对获得性耐药发生的影响 将通过产生HER 2阳性人乳腺癌细胞系的衍生物进行体外分析,所述细胞系将表达 野生型或激酶死亡的介体激酶,并通过分析介体激酶诱变或 选择性CDK 8/19抑制剂治疗对拉帕替尼或紫杉醇适应性耐药的出现。 将使用全面的表型、基因组和转录组学分析来评价药物的作用。 适应和介体激酶抑制对肿瘤促进表型的获得和识别信号 转导途径,其抑制剂可以与CDK 8/19抑制剂组合以增强预防 抗战(2)具有不同介体激酶状态的HER 2阳性人细胞系和一组HER 2- 将选择拉帕替尼和紫杉醇耐药的阳性乳腺癌患者来源的异种移植物(PDX), 体内,比较单独的肿瘤细胞中的介体激酶缺陷和 其在肿瘤和基质细胞中的药理学抑制作用。转录组和表型 分析将用于描述药物选择和介质激酶抑制对基因表达的影响 在肿瘤和基质细胞中。PDX肿瘤的全外显子组测序将揭示介体激酶抑制是否 防止新的耐药肿瘤谱系的出现或抑制耐药细胞的生长 可能预先存在于异构PDX中。(3)介质激酶在药物形成中的作用 还将在鼠Her 2/Neu-driven小鼠乳腺癌细胞中研究耐药性,所述小鼠乳腺癌细胞适于 在体外(如目的1)和体内使用免疫活性和免疫缺陷的同源生长 hosts.该分析将阐明宿主免疫系统对药物适应性的影响以及 介体激酶在此作用。该计划将阐明介质激酶在肿瘤中的作用 适应治疗,在体外和体内,并将表明是否介体激酶抑制药物可能是 能够延长癌症治疗诱导的缓解期。

项目成果

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Eugenia V Broude其他文献

Eugenia V Broude的其他文献

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{{ truncateString('Eugenia V Broude', 18)}}的其他基金

Preventing in vivo resistance to PI3K/AKT/mTOR inhibitors through Mediator kinase inhibition
通过抑制介体激酶来预防体内对 PI3K/AKT/mTOR 抑制剂的耐药性
  • 批准号:
    10602700
  • 财政年份:
    2022
  • 资助金额:
    $ 59.69万
  • 项目类别:
Preventing adaptive drug resistance through Mediator kinase inhibition
通过抑制介体激酶来预防适应性耐药性
  • 批准号:
    10518499
  • 财政年份:
    2022
  • 资助金额:
    $ 59.69万
  • 项目类别:
Potentiating targeted drugs in breast cancer via transcription-regulating kinases
通过转录调节激酶增强乳腺癌靶向药物
  • 批准号:
    9794385
  • 财政年份:
    2019
  • 资助金额:
    $ 59.69万
  • 项目类别:
Selective Targeting of Phosphodiesterase 11A Transcription and Catalytic Activit
磷酸二酯酶 11A 转录和催化活性的选择性靶向
  • 批准号:
    9061733
  • 财政年份:
  • 资助金额:
    $ 59.69万
  • 项目类别:
Selective Targeting of Phosphodiesterase 11A Transcription and Catalytic Activit
磷酸二酯酶 11A 转录和催化活性的选择性靶向
  • 批准号:
    9274311
  • 财政年份:
  • 资助金额:
    $ 59.69万
  • 项目类别:

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口服抗肿瘤药物的获取延迟
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    19591274
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    2007
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    $ 59.69万
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TYROSINE KINASE INHIBITORS AS ANTINEOPLASTIC AGENTS
酪氨酸激酶抑制剂作为抗肿瘤剂
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