Altered LKB1/AMPK Signaling and Chemosensitivity in NSCLC

NSCLC 中 LKB1/AMPK 信号传导和化疗敏感性的改变

• 批准号: 7849563
• 负责人: Wei Zhou
• 金额: $ 22.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7849563
• 关键词: 1-Phosphatidylinositol 3-Kinase; 19p13.3; Antineoplastic Agents; Apoptosis; Benign; Biochemical; Biological Process; Cancer Etiology; Cell Line; Cells; Cellular Stress; Cessation of life; Chromosomes; Clinical; Clinical Trials; Data; Deoxyglucose; Development; Disease; Drug resistance; Epigenetic Process; Farnesyl Transferase Inhibitor; Frequencies; Future; GTPase-Activating Proteins; Genes; Genetic; Goals; Inherited; Laboratories; Link; Literature; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Methylation; Microtubules; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mutation; Non-Small-Cell Lung Carcinoma; Nutrient; Pathway interactions; Patients; Peutz-Jeghers Syndrome; Phosphotransferases; Play; Predictive Value; Predisposition; Primary Neoplasm; Protein-Serine-Threonine Kinases; Proteins; Recurrence; Regulation; Relative (related person); Research Personnel; Resistance; Role; STK11 gene; Sequence Analysis; Signal Pathway; Signal Transduction; Signal Transduction Inhibitor; Small Interfering RNA; Survival Rate; TSC2 gene; Taxane Compound; Testing; Therapeutic Agents; Time; Treatment Efficacy; Tumor Suppressor Proteins; United States; Work; adenylate kinase; base; chemotherapeutic agent; deprivation; disease characteristic; effective therapy; farnesylation; inhibitor/antagonist; insight; loss of function; mTOR protein; mutant; novel; outcome forecast; programs; promoter; response; sensor; standard care; taxane; tumor

LKB1 is a serine/threonine kinase located on chromosome 19p13.3. Inherited mutations in LKB1 give rise to Peutz-Jeghers syndrome, a disorder characterized by benign hemartomas of Gl tract and a predisposition to certain cancers, including lung. While acquired mutations in LKB1 are relatively rare in most sporadic tumor types, more than 30% of NSCLC harbor inactivating mutations in LKB1. Recent progress on the function of LKB1 places this gene at the apex of a novel signaling pathway that ultimately serves to inhibit the mammalian Target of Rapamycin (mTOR). Current evidence supports a model in which LKB1 mediates the suppression of mTOR through the sequential activation of AMP regulated kinase (AMPK) and the tumor suppressor TSC2, overriding PIS kinase/AKT survival signaling under conditions of low energy or nutrient deprivation. Data from the literature and preliminary work from our laboratories indicate that cells with compromised LKB1 function are more resistant to effects of microtubule-targeted chemotherapeutic agents. These data have led us to hypothesize that LKB1 may act as a sensor of microtubule integrity, and that LKB1 mediated suppression of mTOR activity may promote apoptosis in response to microtubule-directed agents. LKB1 is also farnesylated at a CAAX motif in the C-terminus and may be a target of farnesyltransferase inhibitors. Thus, LKB1 and its downstream effectors may represent a convergence point between existing agents like the taxanes that interfere with microtubule dynamics and contemporary signal transduction inhibitors such as the mTOR inhibitors and the farnesyltransferase inhibitors. It is our hypothesis that LKB1/AMPK/TSC2 pathway is a frequent target of inactivation in NSCLC and that the integrity of this pathway is a critical determinant of the sensitivity of NSCLC to selected chemotherapeutic agents. The goals of this proposal are to (i) determine the frequency of LKB1/AMPK signaling pathway alterations in NSCLC, (ii) determine the impact of LKB1/AMPK pathway alterations on the response of NSCLC to selected chemotherapeutic agents, and (iii) determine whether LKB1/AMPK/TSC pathway alterations are predictive of clinical response to therapeutic agents in NSCLC patients. A better understanding of the consequences of altered LKB1/AMPK/TSC2 signaling in NSCLC and its role in chemosensitivity will provide novel insight into the mechanism(s) underlying intrinsic drug resistance and may provide a molecular basis for future implementation of "individualized" therapies.

LKB1 是一种丝氨酸/苏氨酸激酶，位于染色体 19p13.3 上。 LKB1 的遗传突变导致 会导致黑斑息肉综合征，这是一种以胃肠道良性血肿为特征的疾病， 易患某些癌症，包括肺癌。虽然 LKB1 的获得性突变相对罕见 大多数散发性肿瘤类型中，超过 30% 的 NSCLC 含有 LKB1 失活突变。最近的 LKB1 功能的进展将该基因置于新信号通路的顶端，最终 用于抑制哺乳动物雷帕霉素靶点 (mTOR)。目前的证据支持一个模型，其中 LKB1 通过顺序激活 AMP 调节激酶介导 mTOR 抑制 (AMPK) 和肿瘤抑制因子 TSC2，在以下条件下超越 PIS 激酶/AKT 生存信号传导 能量低或营养缺乏。来自文献的数据和我们实验室的初步工作 表明 LKB1 功能受损的细胞对微管靶向的作用更具抵抗力 化疗剂。这些数据使我们推测 LKB1 可能充当 微管完整性，LKB1 介导的 mTOR 活性抑制可能促进细胞凋亡 对微管导向剂的反应。 LKB1 的 C 末端 CAAX 基序也被法尼基化， 可能是法呢基转移酶抑制剂的靶点。因此，LKB1及其下游效应器可能代表 现有药物（如干扰微管动力学的紫杉烷类药物）之间的汇聚点 现代信号转导抑制剂，例如 mTOR 抑制剂和法尼基转移酶 抑制剂。 我们假设 LKB1/AMPK/TSC2 通路是 NSCLC 中常见的失活靶点，并且 该通路的完整性是 NSCLC 对所选药物敏感性的关键决定因素 化疗剂。该提案的目标是 (i) 确定 LKB1/AMPK 的频率 NSCLC 中信号通路的改变，(ii) 确定 LKB1/AMPK 通路改变对 NSCLC 对选定化疗药物的反应，以及 (iii) 确定是否 LKB1/AMPK/TSC 通路改变可预测 NSCLC 治疗药物的临床反应 患者。更好地了解 LKB1/AMPK/TSC2 信号传导改变对 NSCLC 的影响 及其在化学敏感性中的作用将为了解内在药物的机制提供新的见解 耐药性并可能为未来实施“个体化”疗法提供分子基础。