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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：
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.