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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：
Michelle M Williams
金额：
$ 3.01万
依托单位：
VANDERBILT UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/8907328
关键词：
Acute Affect Allografting Apoptosis Apoptotic Aromatase Inhibitors Automobile Driving BCL-2 Protein BCL2 gene BCL2L11 gene Binding Breast Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Cancer Etiology Cell Culture Techniques Cell Death Cell Proliferation Cell Survival Cells Cessation of life Clinical Complex Data Development Disease Progression Endocrine Equilibrium Estrogen Antagonists Estrogen Receptors Estrogens Experimental Models Family Family member Gene Amplification Human Investigation Knowledge Life MCF7 cell MCL1 gene Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Modeling Pathway interactions Patients Pharmaceutical Preparations Protein Family Proteins Publishing Puma Radiation therapy Regulation Reporting Resistance Resistance development Role Series Signal Transduction Tamoxifen Testing Transcript Tumor Suppressor Proteins Up-Regulation Withdrawal Withdrawing Treatments Woman Xenograft procedure cell killing chemotherapy combat deprivation design improved in vivo inhibitor/antagonist interest knock-down leukemia/lymphoma malignant breast neoplasm melanoma member mimetics model development neoplastic cell new therapeutic target novel overexpression pre-clinical protein expression public health relevance response small hairpin RNA small molecule targeted treatment therapy resistant triple-negative invasive breast carcinoma tumor tumor growth tumor initiation

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。