Overcoming Resistance in HER2-positive Breast Cancer

克服 HER2 阳性乳腺癌的耐药性

• 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
• 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

 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）：克服耐药性是寻找乳腺癌治愈方法的主要挑战。对于乳腺癌细胞如何逃避治疗并生存，已经提出了多种机制，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途径逃避细胞凋亡以及利用分解代谢过程（自噬）作为生存机制的能力。我们发现了一种新型 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 HER2/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 HER2 抑制剂治疗等应激，这表明靶向 Hunk 将通过阻断这些逃逸途径来对抗 HER2 抑制的抵抗力。这项研究的长期目标是找到通过克服或避免耐药性来改善乳腺癌治疗的方法。该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 在介导乳腺癌治疗耐药性中的作用。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它如何影响乳腺癌治疗，就可以通过药理学来操纵该激酶的活性，从而产生一种预防和治疗乳腺癌耐药性的创新方法。为了探究这一原理，我们假设 Hunk 通过调节细胞凋亡和自噬这两种细胞死亡途径来促进对 HER2 抑制的抵抗。因此，抑制 Hunk 就会通过阻断这些逃逸机制来克服阻力。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细胞凋亡途径、规范或非规范的自噬途径发出信号，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 HER2 抑制剂耐药性的机制。 (B) 确定 Hunk 是否以 Akt 依赖性方式促进抵抗。目标 2：证明 (A) 靶向 Hunk 会损害曲妥珠单抗和拉帕替尼耐药 BrCa 的肿瘤发生，以及 (B) 评估 JNK 信号传导在促进耐药性方面的作用，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。这项研究的贡献预计将是阐明 Hunk 的新分子活性，这些活性调节细胞生存机制、细胞凋亡和自噬，从而导致乳腺癌对治疗产生耐药性。这些贡献具有重大意义且在概念上具有创新性，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途径。