权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Overcoming Resistance in HER2-positive Breast Cancer

克服 HER2 阳性乳腺癌的耐药性

基本信息

批准号：
9252410
负责人：
Elizabeth S. Yeh
金额：
$ 34.2万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2015-07-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9252410
关键词：
Address Adult Apoptosis Apoptotic Applications Grants Autophagocytosis BCL2 gene Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Cancer cell line CASP3 gene Catabolic Process Cell Count Cell Death Cell Survival Cells Cessation of life Cleaved cell Combined Modality Therapy Data Data Analyses Dose Down-Regulation ERBB2 gene Exhibits Gene Expression Genetic Goals Growth HER2 inhibition Hormonal Human Impairment In Vitro Incidence Intervention KRP protein Knock-out MAPK8 gene Mammary gland Mediating Methods Modeling Molecular Mus Neoplasm Metastasis Pathway interactions Pharmacology Phosphotransferases Preclinical Drug Evaluation Prevention approach Process Protein Kinase Proteins Publishing Refractory Research Resistance Reverse Transcriptase Polymerase Chain Reaction Role Route Sampling Signal Pathway Signal Transduction Staining method Stains Stress Testing Therapeutic Intervention Trastuzumab Work Xenograft procedure base cell transformation combat improved in vivo in vivo Model inhibitor/antagonist innovation killings knock-down lapatinib mRNA Expression malignant breast neoplasm mutant neoplastic cell novel novel therapeutics prevent public health relevance response small hairpin RNA targeted treatment therapy resistant tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Overcoming resistance is a central challenge to finding a cure for breast cancer. A number of mechanisms have been suggested for how breast cancer cells escape treatment and survive, indicating potential novel avenues for therapeutic intervention. These mechanisms include the ability of breast cancer cells to turn on pathways to evade apoptotic cell death and to use the catabolic process, autophagy, as a survival mechanism. We have characterized a novel AMPK-related protein kinase, Hunk, to be critical for breast cancer growth and progression by virtue of its ability to mediate tumor cell survival, and provide evidence that Hunk regulates apoptosis and autophagy. Hunk is upregulated by HER2/neu to promote tumorigenesis, and suppresses apoptosis while promoting autophagy in response to stress such as HER2 inhibitor treatment, indicating that targeting Hunk will combat resistance to HER2 inhibition by blocking these escape pathways. The long-term goal of this research is to identify methods to improve breast cancer treatment by overcoming or evading resistance. The overall objective of this proposal is to demonstrate the molecular mechanisms by which Hunk kinase regulates apoptosis and autophagy to delineate Hunk's role in mediating resistance to breast cancer treatment. The rationale for the proposed research is that, once it is understood the mechanism by which Hunk regulates cell survival and how this impacts breast cancer treatment, the activity of this kinase could be manipulated pharmacologically, resulting in a new and innovative approach for the prevention and treatment of resistance in breast cancers. To pursue this rationale, we hypothesize that Hunk facilitates resistance to HER2 inhibition by regulating two cell death pathways: apoptosis and autophagy. Therefore, inhibiting Hunk will overcome resistance by blocking these escape mechanisms. To test this hypothesis, the following specific aims are proposed. Aim 1: Determine the mechanisms by which Hunk regulates cell survival to mediate resistance to HER2 inhibitors by assessing (A) whether Hunk signals through intrinsic or extrinsic apoptotic pathways and canonical or non-canonical routes of autophagy as well as whether Hunk regulates crosstalk between these pathways. (B) Determine if Hunk facilitates resistance in an Akt-dependent manner. Aim 2: To demonstrate that (A) targeting Hunk impairs tumorigenesis in trastuzumab and lapatinib resistant BrCa and (B) evaluate JNK signaling in promoting resistance because we find that targeting JNK is effective in killing resistant breast cancer cells and collaborates with Hunk targeting. The contribution of the proposed research is expected to be the elucidation of novel molecular activities of Hunk that regulate cell survival mechanisms, apoptosis and autophagy, which cause breast cancers to become resistant to treatment. These contributions are significant and conceptually innovative because they provide novel avenues for pharmacologic intervention in preventing and/or overcoming resistance to breast cancer treatment.

描述(由申请人提供)：克服耐药性是找到乳腺癌治愈方法的核心挑战。关于乳腺癌细胞如何逃脱治疗并存活的许多机制已经被提出，这表明了治疗干预的潜在新途径。这些机制包括乳腺癌细胞开启逃避细胞凋亡的途径的能力，以及利用分解代谢过程自噬作为生存机制的能力。我们已经鉴定了一种新的AMPK相关蛋白激酶，BUNK，它通过调节肿瘤细胞的存活而对乳腺癌的生长和进展起关键作用，并提供了调节细胞凋亡和自噬的证据。Hunk被HER2/neu上调以促进肿瘤的发生，并在应激反应(如HER2抑制剂治疗)时抑制细胞凋亡，同时促进自噬，表明靶向hank将通过阻断这些逃逸途径来对抗对HER2抑制的耐药性。这项研究的长期目标是找出通过克服或逃避耐药性来提高乳腺癌治疗水平的方法。这项建议的总体目标是证明BUNK激酶调节细胞凋亡和自噬的分子机制，以描述BUNK在乳腺癌治疗耐药中的作用。这项拟议研究的基本原理是，一旦了解了BUNK调节细胞存活的机制以及这如何影响乳腺癌的治疗，就可以通过药理学来操纵这种激酶的活性，从而为预防和治疗乳腺癌耐药提供一种新的创新方法。为了探索这一理论基础，我们假设BUNK通过调节两条细胞死亡途径：凋亡和自噬来促进对HER2抑制的抵抗。因此，抑制大块头将通过阻断这些逃逸机制来克服阻力。为了验证这一假设，提出了以下具体目标。目的1：通过评估(A)BUNK信号是通过内源性还是外源性的凋亡途径和典型的或非典型的自噬途径，以及是否调节这些途径之间的串扰，来确定BUNK调节细胞存活以介导对HER2抑制剂的耐药性的机制。(B)确定BUNK是否以Akt依赖的方式促进抵抗。目的：证明(A)靶向BUNK抑制曲妥珠单抗和拉帕替尼耐药的BRCA的肿瘤发生；(B)评估JNK信号在促进耐药性方面的作用，因为我们发现靶向JNK在杀伤耐药的乳腺癌细胞方面是有效的，并且与BUNK靶向协同作用。这项拟议的研究的贡献预计将是阐明BUNK的新分子活性，这些活性调节导致乳腺癌耐药的细胞生存机制、细胞凋亡和自噬。这些贡献具有重大意义和概念上的创新性，因为它们为预防和/或克服乳腺癌治疗耐药性的药物干预提供了新的途径。