Mcl-1 drives resistance of luminal breast cancers to targeted therapies

Mcl-1 导致管腔乳腺癌对靶向治疗产生耐药性

基本信息

  • 批准号:
    8907328
  • 负责人:
  • 金额:
    $ 3.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-01 至 2018-08-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Bcl-2 family proteins use complex intra-family interactions to regulate the intrinsic apoptotic pathway. In particular, anti-apoptotic Bcl-2 famil members (A1, Bcl-2, Bcl-xL, Bcl-w and Mcl-1) inhibit apoptosis by sequestering pro-apoptotic Bcl-2 family members (Bak, Bax, Bid, Bim and Puma). Thus, the balance of pro- to anti-apoptotic Bcl-2 proteins regulates the cellular life-death switch. In cancers, sustained overexpression of anti-apoptotic Bcl-2 family members promotes tumor cell survival. Further, anti-apoptotic Bcl-2 proteins often drive resistance of cancers to chemotherapies and targeted therapies. BH3-mimetics, small molecules designed to sequester the activity of anti-apoptotic Bcl-2 family members, were designed to combat therapeutic resistance caused by anti-apoptotic Bcl-2 proteins. In breast cancers, BH3-mimetics increase treatment-induced tumor cell killing in some but not all tumors. The mechanisms underlying resistance to these BH3-mimetics remain unclear. Our preliminary data suggest that human-derived breast cancer cell lines with MCL1 amplification display limited sensitivity to ABT-263, a BH3-mimetic targeting Bcl-2, Bcl-xL and Bcl-w, and up regulate Mcl-1 protein expression upon treatment with ABT-263. Mcl-1 knock-down increased sensitivity of breast cancer cells to ABT-263, while ectopic Mcl-1 expression enhanced ABT-263 resistance. Given the clinical impact of the Bcl-2 family in breast and other cancers, it is critical to investigate further the role of Mcl-1 in ABT-263 resistance, which we wil study in Aim 1. We further propose to study how Mcl-1 affects response of breast cancers to estrogen deprivation. Approximately 65% of breast cancers are dependent upon estrogen receptor-a (ERa) signaling, and thus are treated with ERa-targeting agents. The impact of Mcl-1 remains under-studied in this context. Our preliminary data show that Mcl-1 levels increase upon long term estrogen deprivation (LTED), a model used to mimic the estrogen-depleted conditions caused by treatment with aromatase inhibitors. We designed to combat therapeutic resistance caused by anti-apoptotic Bcl-2 proteins in Aim 2. Together, these studies will determine if Mcl-1 inhibitors, including a novel Mcl-1- specific BH3-mimetic developed by our collaborator, could be exploited clinically to improve tumor cell killing and to increase patient survival.
 描述(由申请人提供):Bcl-2家族蛋白使用复杂的家族内相互作用来调节内在凋亡途径。特别地,抗凋亡Bcl-2家族成员(A1、Bcl-2、Bcl-xL、Bcl-w和Mcl-1)通过隔离促凋亡Bcl-2家族成员(巴克、Bax、Bid、Bim和Puma)来抑制凋亡。因此,促凋亡Bcl-2蛋白与抗凋亡Bcl-2蛋白的平衡调节细胞生死开关。在癌症中,抗凋亡Bcl-2家族成员的持续过表达促进肿瘤细胞存活。此外,抗凋亡Bcl-2蛋白通常会导致癌症对化疗和靶向治疗产生抗性。BH 3-模拟物,设计用于隔离抗凋亡Bcl-2家族成员的活性的小分子,被设计用于对抗由抗凋亡Bcl-2蛋白引起的治疗抗性。在乳腺癌中,BH 3模拟物在一些但不是所有肿瘤中增加治疗诱导的肿瘤细胞杀伤。对这些BH 3-模拟物的抗性的潜在机制仍不清楚。 我们的初步数据表明,MCL 1扩增的人源性乳腺癌细胞系对ABT-263(一种靶向Bcl-2、Bcl-xL和Bcl-w的BH 3模拟物)显示出有限的敏感性,并在用ABT-263处理后上调Mcl-1蛋白表达。Mcl-1敲低增加了乳腺癌细胞对ABT-263的敏感性,而异位Mcl-1表达增强了ABT-263的耐药性。鉴于Bcl-2家族在乳腺癌和其他癌症中的临床影响,进一步研究Mcl-1在ABT-263抗性中的作用至关重要,我们将在目标1中研究。 我们进一步建议研究Mcl-1如何影响乳腺癌对雌激素剥夺的反应。大约65%的乳腺癌依赖于雌激素受体-α(ER α)信号传导,因此用ER α靶向剂治疗。在这种情况下,Mcl-1的影响仍然研究不足。我们的初步数据显示,Mcl-1水平增加后,长期雌激素剥夺(LTED),用于模拟雌激素耗竭的条件下,由芳香酶抑制剂治疗引起的模型。我们设计对抗Aim 2中抗凋亡Bcl-2蛋白引起的治疗抗性。总之,这些研究将确定Mcl-1抑制剂,包括我们的合作者开发的新型Mcl-1特异性BH 3模拟物,是否可以在临床上用于改善肿瘤细胞杀伤和增加患者存活率。

项目成果

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Michelle M Williams其他文献

Michelle M Williams的其他文献

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{{ truncateString('Michelle M Williams', 18)}}的其他基金

Targeting heme metabolism to initiate an immune response against breast cancer liver metastasis
靶向血红素代谢启动针对乳腺癌肝转移的免疫反应
  • 批准号:
    10669286
  • 财政年份:
    2022
  • 资助金额:
    $ 3.01万
  • 项目类别:
Targeting heme metabolism to initiate an immune response against breast cancer liver metastasis
靶向血红素代谢启动针对乳腺癌肝转移的免疫反应
  • 批准号:
    10523842
  • 财政年份:
    2022
  • 资助金额:
    $ 3.01万
  • 项目类别:
Impact of heme catabolism on triple negative breast cancer metastasis via immune-suppression
血红素分解代谢通过免疫抑制对三阴性乳腺癌转移的影响
  • 批准号:
    9910781
  • 财政年份:
    2020
  • 资助金额:
    $ 3.01万
  • 项目类别:
Mcl-1 drives resistance of luminal breast cancers to targeted therapies
Mcl-1 导致管腔乳腺癌对靶向治疗产生耐药性
  • 批准号:
    9145078
  • 财政年份:
    2015
  • 资助金额:
    $ 3.01万
  • 项目类别:

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