Negative feedback signaling in tyrosine kinase-driven leukemia

酪氨酸激酶驱动的白血病中的负反馈信号

• 批准号: 8681396
• 负责人: Markus Müschen
• 金额: $ 31.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681396
• 关键词: ABL1 gene; Acute; Acute Myelocytic Leukemia; Affect; Attenuated; Biological Markers; Breast; Cell Death; Cells; Chronic Myeloid Leukemia; Clinical; Complement; Cytokine Inducible SH2-Containing Protein; Data; Dependence; Dependency; Derivation procedure; Development; Distal; Drug resistance; ERBB2 gene; Family; Feedback; Genetic; Goals; Human; Hypermethylation; Imatinib; JAK2 gene; Lung Adenocarcinoma; MAPK3 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mammary Neoplasms; Mediating; Mediator of activation protein; Modeling; Mus; Normal Cell; Oncogenic; Outcome; Pathway interactions; Patients; Peptides; Phenotype; Phosphoric Monoester Hydrolases; Protein Dephosphorylation; Protein Tyrosine Kinase; Reaction; Regulation; Resistance; Role; Sampling Studies; Sequential Treatment; Signal Transduction; Solid Neoplasm; Specificity; Testing; Therapeutic; Transplant Recipients; Treatment Protocols; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Validation; Work; Xenograft procedure; base; chemotherapy; exhaustion; fitness; improved; inhibitor/antagonist; leukemia; mouse model; neoplastic cell; new therapeutic target; non-oncogenic; novel; oxidation; pre-clinical; pressure; prevent; promoter; public health relevance; research study; sarcoma; self-renewal; small molecule; success; therapeutic target; tumor

DESCRIPTION (provided by applicant): Tyrosine kinase inhibitors (TKIs) against oncogenic tyrosine kinases (OTK; e.g. BCR-ABL1, EGFRL858R, ERBB2) have created a new era of treatment for OTK leukemia and solid tumors and have substantially improved clinical outcome. Despite their clinical success in chronic myeloid leukemia (CML), resistance to TKIs, such as Imatinib, is a common outcome in most OTK-malignancies. While combination of TKI with conventional chemotherapy results in prolonged survival for most OTK-malignancies, for a large group of patients, no curative treatment option is available. In preliminary work for this proposal we have found that two negative feedback regulators (SPRY2 and DUSP6) are expressed at high levels in OTK-malignancies but not in normal cells or tumor cells lacking an oncogenic tyrosine kinase. The inhibitory linker molecule Sprouty2 (SPRY2) attenuates signal transduction immediately downstream of the oncogenic tyrosine kinase, the Dual Specific Phosphatase DUSP6 interferes with distal signal transduction by dephosphorylation of ERK1/2. Expression levels of these molecules are dependent on the signaling strength of the oncogenic tyrosine kinase and are completely suppressed upon TKI-treatment. Molecules of the Sprouty- and DUSP- families of negative feedback mediators are often inactivated through deletion or promoter hypermethylation in Non- tyrosine kinase tumors but not in OTK-malignancies. Given that SPRY2- and DUSP6-mediated negative feedback signaling was highly active in all OTK-tumor samples studied, we performed experiments that demonstrated that OTK-leukemia cells indeed critically depend on continuous active negative feedback signaling to calibrate otherwise overwhelming tyrosine kinase signaling. In this proposal, we will test the central hypothesis that negative feedback regulators represent a fundamentally novel class of therapeutic targets for the treatment of OTK-leukemias and -solid tumors. The central goal of this proposal is to build a fundamental understanding of how blockade of negative feedback mechanistically leads to cell death in OTK-malignancies (Aims 1-2), and to leverage this mechanistic information towards the development of a new therapy concept based on alternating treatment schedules between TKIs and negative feedback inhibitors (NFIs; Aim 3).

描述（由申请人提供）：针对致癌酪氨酸激酶（OTK;例如BCR-ABL1，EGFRL858R，ERBB2）针对致癌酪氨酸激酶的酪氨酸激酶抑制剂（TKIS）为OTK白血病和实体瘤创造了一个新的治疗时代，并具有实质上改善的临床结果。尽管在慢性髓样白血病（CML）方面取得了临床成功，但在大多数OTK - 癌症中，对TKIS的抗性（例如伊马替尼）是一个常见的结果。尽管TKI与常规化学疗法的结合可导致大多数OTK - 癌症的生存率延长，但对于大量患者而言，没有可用的治疗方法。在该提案的初步工作中，我们发现两个负反馈调节剂（SPRY2和DUSP6）在OTK-MALIGNANC中高水平表达，但在正常细胞或缺乏致癌酪氨酸激酶的肿瘤细胞中却没有表达。抑制性接头分子sprouty2（SPRY2）会减弱信号转导的信号转导，立即在致癌酪氨酸激酶的下游，双重特异性磷酸酶DUSP6通过ERK1/2的去磷酸化干扰了远端信号转导的远端信号转导。这些分子的表达水平取决于致癌酪氨酸激酶的信号传导强度，并在TKI治疗后完全抑制。负反馈介质的发芽和DUSP家族的分子通常通过非酪氨酸激酶肿瘤中的缺失或启动子过度甲基化灭活，而不是在OTK - 甲基化中。鉴于SPRY2-和DUSP6介导的负反馈信号在所研究的所有OTK肿瘤样品中都高度活跃，我们进行了实验，这些实验表明OTK-白血病细胞确实在严格地依赖于连续的活性负反馈信号传导以校准，否则校准了诸如压倒性的酪氨酸激酶信号传导。在此提案中，我们将检验一个中心假设，即负反馈调节剂代表了治疗OTK -Leukemias和-solid肿瘤的根本新型治疗靶标。该提案的核心目的是建立对负面反馈的封锁方式的基本理解，如何在机械上导致OTK-MALIGNANCE（目标1-2）中的细胞死亡，并利用这种机械信息来发展基于TKIS和负面反馈抑制剂之间的交替治疗时间表的新疗法概念（NFIS; AIM 3）。