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：
9145078
负责人：
Michelle M Williams
金额：
$ 2.67万
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 2017-08-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9145078
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 Receptor alpha 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 agent 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 家族蛋白利用复杂的家族内相互作用来调节内在的凋亡途径，特别是抗凋亡 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 (Bak、Bax、Bid、Bim 和 Puma) 来抑制细胞凋亡，从而实现促凋亡的平衡。抗凋亡 Bcl-2 蛋白调节细胞生死转换在癌症中，抗凋亡 Bcl-2 家族成员的持续过度表达可促进肿瘤细胞存活。此外，抗凋亡 Bcl-2 蛋白通常会促进癌症的抵抗。化疗和靶向治疗是一种旨在隔离抗凋亡 Bcl-2 家族成员活性的小分子，旨在对抗由 BH3 引起的治疗耐药。在乳腺癌中，BH3 模拟物会增加某些但不是所有肿瘤中治疗诱导的肿瘤细胞杀伤作用，我们的初步数据表明，这些 BH3 模拟物的耐药机制仍不清楚。 MCL1 扩增的癌细胞系对 ABT-263（一种靶向 Bcl-2、Bcl-xL 和 Bcl-w 的 BH3 模拟物）表现出有限的敏感性，并上调 Mcl-1 蛋白表达考虑到 Bcl-2 家族在乳腺癌和其他疾病中的临床影响，用 ABT-263 治疗后，Mcl-1 敲除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 耐药性。癌症，进一步研究 Mcl-1 在 ABT-263 耐药中的作用至关重要，我们将在目标 1 中研究这一点。我们进一步建议研究 Mcl-1 如何影响乳腺癌对雌激素剥夺。大约 65% 的乳腺癌依赖于雌激素受体-a (ERa) 信号传导，因此需要使用 ERa 靶向药物进行治疗。我们的初步数据尚未得到充分研究。表明 Mcl-1 水平在长期雌激素剥夺 (LTED) 后增加，这是一种用于模拟芳香酶抑制剂治疗引起的雌激素耗尽状况的模型，我们旨在对抗由芳香酶抑制剂引起的治疗抵抗。目标 2 中的抗凋亡 Bcl-2 蛋白。这些研究将共同确定 Mcl-1 抑制剂（包括我们的合作者开发的新型 Mcl-1 特异性 BH3 模拟物）是否可以在临床上利用来改善肿瘤细胞杀伤并提高患者的生存率。