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：
8882873
负责人：
Elizabeth S. Yeh
金额：
$ 31.48万
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/8882873
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 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 Human In Vitro Incidence Intervention JNK-activating protein kinase KRP protein Knock-out MAPK8 gene Mammary gland Mediating Methods Modeling Molecular Mus Neoplasm Metastasis Oncogenes Pathway interactions 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 caspase-3 cell transformation combat improved in vivo in vivo Model inhibitor/antagonist innovation killings lapatinib mRNA Expression malignant breast neoplasm mutant neoplastic cell novel novel therapeutics prevent public health relevance response small hairpin RNA targeted treatment 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。乳腺癌细胞如何逃避治疗和存活的机制已经提出了许多建议，这表明了潜在的新途径的治疗干预。这些机制包括乳腺癌细胞开启途径以逃避凋亡细胞死亡和使用分解代谢过程自噬作为生存机制的能力。我们已经表征了一种新的AMPK相关蛋白激酶，Hunk，由于其介导肿瘤细胞存活的能力，对乳腺癌的生长和进展至关重要，并提供了Hunk调节细胞凋亡和自噬的证据。Hunk被HER 2/neu上调以促进肿瘤发生，并抑制细胞凋亡，同时促进自噬以响应诸如HER 2抑制剂治疗的应激，这表明靶向Hunk将通过阻断这些逃逸途径来对抗对HER 2抑制的抗性。这项研究的长期目标是确定通过克服或避免耐药性来改善乳腺癌治疗的方法。本提案的总体目标是证明Hunk激酶调节细胞凋亡和自噬的分子机制，以描述Hunk在介导乳腺癌治疗抗性中的作用。这项研究的基本原理是，一旦了解了Hunk调节细胞存活的机制以及这如何影响乳腺癌治疗，这种激酶的活性就可以被操纵，从而为预防和治疗乳腺癌耐药性提供了一种新的创新方法。为了追求这一基本原理，我们假设Hunk通过调节两种细胞死亡途径：凋亡和自噬来促进对HER 2抑制的抵抗。因此，抑制Hunk将通过阻断这些逃逸机制来克服抗性。为了检验这一假设，提出了以下具体目标。目标1：通过评估（A）Hunk是否通过内在或外在凋亡途径和自噬的经典或非经典途径发出信号以及Hunk是否调节这些途径之间的串扰，确定Hunk调节细胞存活以介导对HER 2抑制剂的抗性的机制。(B)确定Hunk是否以Akt依赖性方式促进耐药性。目标二：为了证明（A）靶向Hunk损害曲妥珠单抗和拉帕替尼耐药BrCa中的肿瘤发生和（B）评价JNK信号传导促进耐药，因为我们发现靶向JNK可有效杀死耐药乳腺癌细胞并与Hunk靶向协同作用。拟议研究的贡献预计将是阐明Hunk的新分子活性，这些活性调节细胞存活机制，细胞凋亡和自噬，导致乳腺癌对治疗产生抗药性。这些贡献是重要的和概念上的创新，因为它们提供了新的途径，在预防和/或克服乳腺癌治疗的耐药性的药物干预。