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

基本信息

批准号：
9311090
负责人：
Robert Schneider
金额：
$ 42.35万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9311090
关键词：
Adjuvant Therapy Animals Aromatase Inhibitors Biopsy Specimen Breast Cancer Cell Breast Cancer cell line Breast cancer metastasis Cell Line Cell Survival Cells Cessation of life Disease EGFR Protein Overexpression EIF4EBP1 gene Endocrine Epidermal Growth Factor Receptor Estrogen Receptor alpha Estrogen Receptors Estrogen receptor positive FRAP1 gene Genetic Translation Indolent MAP Kinase Gene Mediating Mediator of activation protein Messenger RNA Modeling Neoplasm Metastasis 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 pre-clinical research response biomarker small molecule therapeutic target tumor tumor growth

项目摘要

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他莫昔芬的抗内分泌治疗引起的。仍然是 ER+ 乳腺癌辅助治疗的基石，特别是绝经前女性，但也有许多人在绝经后接受芳香酶抑制剂治疗后出现这种情况。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因此，内分泌抵抗性 ER+ 乳腺癌仍然是 15 年内的转移性疾病之一。事实上，对他莫昔芬的初始或获得性耐药是乳腺癌转移和死亡的主要原因。超过一半的 ER+ 乳腺癌死亡病例涉及逆转对他莫昔芬治疗的耐药性。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) 途径，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重新定位该轴以治疗他莫昔芬耐药的 ER+ 乳腺癌。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。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，我们展示了它们在耐药性中的重要性。他莫昔芬耐药性的两个效应器是。翻译起始因子 eIF4E 的抑制剂，称为 4E-BP1，以及 eIF4E 的磷酸化其 ERK 相关激酶 MNK1 的激活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。我的团队和其他人的许多研究表明，将核糖体加载到 mRNA 上会增加。 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。