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: 7481156
• 负责人: Wei Zhou
• 金额: $ 21.38万
• 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/7481156
• 关键词: 1-Phosphatidylinositol 3-Kinase; 19p13.3; AICA ribonucleotide; Antineoplastic Agents; Apoptosis; Benign; Biochemical; Biological Process; Cancer Etiology; Cell Line; Cells; Cessation of life; Chromosomes; Clinical; Clinical Trials; Condition; 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; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphotransferases; Play; Polymerase Chain Reaction; 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; Sirolimus; Small Interfering RNA; Standards of Weights and Measures; Stress; Survival Rate; TSC2 gene; Taxane Compound; Testing; Therapeutic Agents; Time; Tumor Suppressor Proteins; United States; Work; adenylate kinase; base; chemotherapeutic agent; deprivation; disease characteristic; farnesylation; inhibitor/antagonist; insight; loss of function; mutant; novel; outcome forecast; programs; promoter; response; sensor; 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是位于19p13.3染色体上的丝氨酸/苏氨酸激酶。 LKB1中的继承突变给出 崛起到Peutz-Jeghers综合征，这种疾病为特征于GL段和A 包括肺在内的某些癌症的易感性。虽然在LKB1中获得的突变相对较少 大多数零星的肿瘤类型，超过30％的NSCLC在LKB1中灭活突变。最近的 LKB1功能的进展将该基因放置在新的信号通路的顶点 可抑制雷帕霉素（MTOR）的哺乳动物靶标。当前证据支持一个模型 LKB1通过AMP调节激酶的顺序激活介导MTOR的抑制 （AMPK）和肿瘤抑制剂TSC2，在条件下的PIS激酶/AKT生存信号传导 低能量或营养剥夺。来自我们实验室的文献和初步工作的数据 表明具有受损LKB1功能的细胞对微管靶向的影响更具耐药性 化学治疗剂。这些数据使我们假设LKB1可能是 微管完整性，LKB1介导的MTOR活性抑制可能会促进凋亡 对微管定向剂的响应。 LKB1在C末端的CAAX基序中也是Farnesyl的， 可能是Farnesylsylansfer酶抑制剂的靶标。因此，LKB1及其下游效应子可能代表 现有代理之间的融合点，例如干扰微管动力学的紫杉烷和 当代信号转导抑制剂，例如MTOR抑制剂和Farnesylsylansfransferase 抑制剂。 我们的假设是LKB1/AMPK/TSC2途径是NSCLC和 该途径的完整性是NSCLC敏感性的关键决定因素 化学治疗剂。该建议的目标是（i）确定LKB1/AMPK的频率 NSCLC中的信号通路改变，（ii）确定LKB1/AMPK途径改变对 NSCLC对选定的化学治疗剂的反应，（iii）是否确定 LKB1/AMPK/TSC途径改变是对NSCLC治疗剂的临床反应的预测 患者。更好地理解NSCLC中改变LKB1/AMPK/TSC2信号的后果 它在化学敏感性中的作用将提供对固有药物基本机制的新见解 抗性，可能为未来实施“个性化”疗法提供分子基础。