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：
9379089
负责人：
Elizabeth S. Yeh
金额：
$ 5.36万
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/9379089
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（适用提供）：克服抗性是找到治疗乳腺癌的核心挑战。已经提出了许多机制，即乳腺癌细胞如何逃脱治疗并存活，这表明了潜在的治疗干预途径。这些机制包括乳腺癌细胞开启途径以逃避凋亡细胞死亡的能力，并将自动噬菌的分解代谢过程作为生存机制。我们表征了一种新型AMPK相关的蛋白激酶Hunk，这对于乳腺癌的生长和进展至关重要，凭借其介导肿瘤细胞存活的能力，并提供了大块头调节凋亡和自噬的证据。 HER2/NEU对HUNK进行了更新，以促进肿瘤发生，并抑制凋亡，同时促进自噬，以应对HER2抑制剂治疗等压力，这表明靶向Hunk将通过阻止这些逃生途径来应对对HER2抑制的抵抗力。这项研究的长期目标是通过克服或逃避抗性来确定改善乳腺癌治疗的方法。该提案的总体目的是证明大块激酶调节细胞凋亡和自噬的分子机制，以描述大块头在介导对乳腺癌治疗的耐药性中的作用。拟议研究的理由是，一旦理解了大块调节细胞存活的机制，以及这如何影响乳腺癌治疗，该激酶的活性就可以被药物处理，从而为预防乳腺癌耐药性预防和治疗一种新的和创新的方法。为了提出这一基本原理，我们假设大块通过确定两种细胞死亡途径来促进对HER2抑制的抵抗：凋亡和自噬。因此，抑制大块将通过阻止这些逃生机制来克服抵抗力。为了检验这一假设，提出了以下特定目标。目标1：通过评估（a）评估（a）通过固有或外在的凋亡途径以及自动噬菌体的规范或非传统途径来调节培养基对HER2抑制剂的细胞存活的机制，以及是否会调节这些途径之间的串扰。（b）确定块状是否以Akt依赖性方式促进了抵抗。目的2：证明（a）靶向大块损害曲妥珠单抗和拉帕替尼耐药的BRCA中的肿瘤发生，以及（b）评估JNK信号在促进抗药性方面，因为我们发现靶向JNK有效地杀死了抗性乳腺癌细胞并与Hunk Targeting合作。拟议研究的贡献预计将是对调节细胞存活机制，凋亡和自噬的大块分子活性的阐明，这会导致乳腺癌对治疗具有抵抗力。这些贡献在概念上具有重要的创新性，因为它们为防止和/或克服对乳腺癌治疗的耐药性提供了新的途径。