the mTOR translational control pathway in tamoxifen resistant ER+ breast cancer

他莫昔芬耐药 ER 乳腺癌中的 mTOR 翻译控制通路

• 批准号: 10166782
• 负责人: Robert Schneider
• 金额: $ 44.04万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166782
• 关键词: Adjuvant Therapy; Animals; Aromatase Inhibitors; Biopsy Specimen; Breast Cancer Cell; Breast Cancer cell line; Breast cancer metastasis; Cell Line; Cell Survival; Cessation of life; Disease; EGFR Protein Overexpression; EIF4EBP1 gene; Endocrine; Epidermal Growth Factor Receptor; Estrogen Receptor alpha; Estrogen Receptors; Estrogen Therapy; Estrogen receptor positive; FRAP1 gene; Genetic Translation; Indolent; MAP Kinase Gene; Mediating; Mediator of activation protein; Messenger RNA; Pathway interactions; Peptide Initiation Factors; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Postmenopause; Premenopause; Protein Kinase; Recurrence; Relapse; Resistance; Ribosomes; Role; Signal Transduction; Tamoxifen; Testing; Toxic effect; Translations; Tumorigenicity; Woman; hormone therapy; inhibitor/antagonist; malignant breast neoplasm; mortality; neoplastic cell; novel; patient derived xenograft model; pre-clinical research; response biomarker; small molecule; therapeutic target; tumor; tumor growth

Project Summary. Estrogen receptor positive (ER+) breast cancers comprise the majority (~70-80%) of breast cancers, the majority of late recurrences emanating from indolent or dormant breast cancer, and the majority of breast cancer deaths resulting from metastatic disease. Anti-endocrine therapy with tamoxifen remains the cornerstone of adjuvant therapy for ER+ breast cancers, particularly in premenopausal women, but also following treatment with aromatase inhibitors in the post-menopausal setting. Nevertheless, many women do not respond to tamoxifen in initial therapy, and of those that do, one third will relapse with resistant and metastatic disease within 15 years. Endocrine resistant ER+ breast cancers therefore remain one of the major causes of breast cancer metastasis and mortality. In fact, initial or acquired resistance to tamoxifen is involved in more than half of all ER+ breast cancer deaths. Reversing resistance to tamoxifen therapy is a crucial overarching breast cancer challenge. We provide preclinical research demonstrating the discovery of a crucial axis that provides tamoxifen resistance to ER+ breast cancer cells mediated by the epidermal growth factor receptor (EGFR)/estrogen receptor α (ERα) pathways, and their impact on selective mRNA translation through the kinase mTOR. Moreover, we demonstrate that there are several experimental drugs developed for other indications that can be repurposed to target this axis for the treatment of tamoxifen resistant ER+ breast cancers. Tamoxifen is an estrogen receptor antagonizing small molecule used for treatment for ER+ breast cancer worldwide. Resistance is well established to commonly involve overexpression of EGFRs on breast cancer cells, and hyper-activation or increased signaling of the MAPK-ERK and PI3K-Akt-mTOR pathways. We have now identified two novel hyperactivated mediators of resistance to tamoxifen therapy that lie at the intersection of these key pathways, and we show their importance in resistance. The two effectors of tamoxifen resistance are the inhibitor of translation initiation factor eIF4E, known as 4E-BP1, and the phosphorylation of eIF4E by hyper- activation of its ERK associated kinase, MNK1. Both are therapeutic targets for existing experimental drugs developed for other purposes with good toxicity profiles. eIF4E comprises the basic translation component for loading ribosomes onto mRNAs. Many studies by my group and others have shown that increased phosphorylation of eIF4E is controlled by the ERK-MNK1 pathway, and its increased abundance is controlled by the mTOR/4E-BP1 pathway, which selectively upregulates translation of specific mRNAs required for survival, proliferation and metastasis of breast cancer cells.

项目摘要。雌激素受体阳性 (ER+) 乳腺癌占大多数 (~70-80%) 乳腺癌，大多数晚期复发源于惰性或休眠乳腺癌，以及 大多数乳腺癌死亡是由转移性疾病引起的。他莫昔芬抗内分泌治疗 仍然是 ER+ 乳腺癌辅助治疗的基石，特别是绝经前女性， 而且在绝经后接受芳香酶抑制剂治疗后也会出现这种情况。尽管如此，许多 女性在初始治疗中对他莫昔芬没有反应，而在有反应的女性中，三分之一会因耐药而复发 以及 15 年内发生转移性疾病。因此，内分泌抵抗性 ER+ 乳腺癌仍然是最常见的乳腺癌之一。 乳腺癌转移和死亡的主要原因。事实上，对他莫昔芬的初始或获得性耐药性是 超过一半的 ER+ 乳腺癌死亡病例。逆转他莫昔芬治疗的耐药性是 至关重要的乳腺癌挑战。 我们提供临床前研究，证明发现了提供他莫昔芬的关键轴 表皮生长因子受体 (EGFR)/雌激素介导的对 ER+ 乳腺癌细胞的耐药性 受体 α (ERα) 通路及其对通过激酶 mTOR 选择性 mRNA 翻译的影响。 此外，我们证明有几种针对其他适应症开发的实验药物可以 被重新利用以靶向该轴来治疗他莫昔芬耐药的 ER+ 乳腺癌。他莫昔芬是一种 雌激素受体拮抗小分子，用于治疗全球 ER+ 乳腺癌。 众所周知，耐药性通常涉及乳腺癌细胞上 EGFR 的过度表达，并且 MAPK-ERK 和 PI3K-Akt-mTOR 通路过度激活或信号传导增强。我们现在有 确定了两种新型的对他莫昔芬治疗产生耐药性的过度激活介质，它们位于 这些关键途径，我们展示了它们在抵抗中的重要性。他莫昔芬耐药的两个效应器是 翻译起始因子 eIF4E 的抑制剂，称为 4E-BP1，以及 eIF4E 的磷酸化 激活其 ERK 相关激酶 MNK1。两者都是现有实验药物的治疗靶点 为其他目的而开发，具有良好的毒性特征。 eIF4E 包含基本翻译组件 将核糖体加载到 mRNA 上。我的团队和其他人的许多研究表明， eIF4E 的磷酸化受 ERK-MNK1 通路控制，其丰度增加受到控制 通过 mTOR/4E-BP1 途径，选择性上调所需的特定 mRNA 的翻译 乳腺癌细胞的存活、增殖和转移。

项目成果

RIVET: comprehensive graphic user interface for analysis and exploration of genome-wide translatomics data.

• DOI: 10.1186/s12864-018-5166-z
• 发表时间: 2018-11-08
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Ernlund AW;Schneider RJ;Ruggles KV
• 通讯作者: Ruggles KV

Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming.

• DOI: 10.1101/gad.305631.117
• 发表时间: 2017-11-15
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Geter PA;Ernlund AW;Bakogianni S;Alard A;Arju R;Giashuddin S;Gadi A;Bromberg J;Schneider RJ
• 通讯作者: Schneider RJ