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: 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
• 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

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+）乳腺癌包括大多数（〜70-80％） 乳腺癌，大多数来自懒惰或休眠乳腺癌产生的近期回报，以及 大多数由转移性疾病引起的乳腺癌死亡。他莫昔芬的抗分泌疗法 仍然是ER+乳腺癌的可调节疗法的基石，特别是在绝经前妇女中， 而且在绝经后环境中用芳香酶抑制剂进行治疗。尽管如此，很多 妇女在初始疗法中不对他昔佛剂反应 15年内转移性疾病。因此，内分泌ER+乳腺癌仍然是其中之一 乳腺癌转移和死亡率的主要原因。实际上，对他莫昔芬的初始或获得的抗性为 涉及所有ER+乳腺癌死亡的一半以上。逆转对他莫昔芬治疗的抵抗力是 至关重要的总体乳腺癌挑战。 我们提供临床前研究，证明发现了一个至关重要的轴，该轴提供了他莫昔芬 对表皮生长因子受体（EGFR）/雌激素介导的ER+乳腺癌细胞的抗性 受体α（ERα）途径及其对通过激酶MTOR的选择性mRNA翻译的影响。 此外，我们证明有几种用于其他指示的实验药物可以 重新使用以靶向该轴以治疗他莫昔芬耐药+乳腺癌。他莫昔芬是一个 雌激素受体拮抗用于全球ER+乳腺癌治疗的小分子。 耐药性已得到很好的确定，通常涉及EGFR在乳腺癌细胞上的过表达，并且 MAPK-ERK和PI3K-AKT-MTOR途径的过度激活或增加信号传导。我们现在有 确定了两个新型的过度活化的对他昔佛疗法的抗性的介体，这是在 这些关键途径，我们表明它们在抵抗中的重要性。他莫昔芬抵抗的两个影响是 翻译起始因子EIF4E的抑制剂（称为4E-BP1），以及通过超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标 为其他目的而开发的具有良好的毒性特征。 EIF4E包括 将核糖体装在mRNA上。我小组和其他人的许多研究表明， EIF4E的磷酸化受ERK-MNK1途径控制，并且其丰度增加了 通过MTOR/4E-BP1途径，它有选择地上调了所需的特定mRNA的翻译 乳腺癌细胞的生存，增殖和转移。