Novel Strategy for Lung Cancer Treatment Using IGF-1R Inhibitor

使用 IGF-1R 抑制剂治疗肺癌的新策略

• 批准号: 8051592
• 负责人: HO-YOUNG LEE
• 金额: $ 17.03万
• 依托单位: SEOUL NATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051592
• 关键词: Address; Adenocarcinoma; Adenoviruses; Adrenergic Receptor; Agonist; Alveolus; Arrestins; Binding Sites; Butanones; Cancer Etiology; Cancer cell line; Cessation of life; Complex; Dasatinib; Development; Diagnosis; Disease; Distal; Ensure; Epidermal Growth Factor Receptor; Epithelium; Exhibits; Exposure to; Focal Adhesion Kinase 1; G protein coupled receptor kinase; Gene Amplification; Growth; Growth Factor; Growth and Development function; Hormones; Human; Hyperactive behavior; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Integrins; Intervention; Ligands; Link; Lung; Lung Neoplasms; Maintenance; Malignant neoplasm of lung; Mediating; Methods; Modeling; Monoclonal Antibodies; Mus; Mutation; Neoplasm Metastasis; Nicotinic Receptors; Non-Small-Cell Lung Carcinoma; Nude Mice; Pathway interactions; Patients; Phosphorylation; Prognostic Factor; Protein Binding; Protein Tyrosine Kinase; Pulmonary Surfactant-Associated Protein C; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Reporting; Resistance; Risk; Role; SRC gene; Scaffolding Protein; Signal Transduction; Signaling Molecule; Smoker; Somatomedins; Specimen; Staging; Stimulus; Stress; Systemic Therapy; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Tobacco; Tobacco smoke; Tobacco-Associated Carcinogen; Transgenes; Transgenic Mice; Tyrosine; Tyrosine Kinase Inhibitor; United States; Virus; advanced disease; autocrine; base; cancer cell; cancer therapy; humanized monoclonal antibodies; inhibitor/antagonist; lung carcinogenesis; mouse model; mutant; novel strategies; overexpression; paracrine; prevent; protein-tyrosine kinase c-src; public health relevance; receptor; receptor expression; response; small hairpin RNA; src-Family Kinases; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): New methods for treating non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths in the United States, are needed. Deregulated signaling through the IGF-1 receptor (IGF-1R) has been linked to development, maintenance, and progression of cancer. Hence, one potentially effective therapeutic strategy for patient with NSCLC is to target the insulin-like growth factor (IGF) signaling axis. One potential concern about the use of IGF-1R-targeted agents in lung cancer therapy, however, is overexpression/hyperactivity of Src-family kinases (SFKs), which could be activated by a myriad of cellular stimuli, including overexpression and/or mutation of growth factors and their receptors, components of tobacco smoke, hormones, alterations in integrin regulation and overexpression of focal adhesion kinase. We recently found evidence for the involvement of Src-family kinases (SFKs) in the activation of IGF-1R in NSCLC. The potent tobacco carcinogen (TC) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acting as an agonist for 2-adrenergic receptor (2-AR) and nicotinic acetylcholine receptors, induced IGF-1R phosphorylation and proliferative, angiogenic, invasive activities in NSCLC cell lines, which were abrogated by inhibitors of SFK or 2-AR but not by anti-IGF-1R monoclonal antibody, IGF-1R tyrosine kinase inhibitor, or nAChR antagonists. These findings suggest that SFKs activated via signaling involving NNK-stimulated 2-AR induced IGF-1R phosphorylation in an IGF-1R tyrosine kinase-independent manner, providing an alternative intracellular mechanism for IGF-1R activation thus counteracting the antitumor action of IGF-1R-targeted intervention. Sustained inhibition of IGF-1R by IGF-1R-targeted agents induced activation of c-Src, further implicating SFKs in resistance to IGF-1R-targeted therapy. Thus, overexpression and hyperactivity of SFKs in NSCLC could be a potential obstacle to the use of IGF-1R-targeted agents in patients with NSCLC. Accordingly, integration of SFK-targeted agents could circumvent potential resistance towards IGF-1R-targeted therapy. In our ongoing efforts to determine the mechanisms underlying NNK-induced activation of IGF-1R signaling, we found that NNK stimulation resulted in the association of IGF-1R and RACK1, a scaffold protein that binds to a number of signaling molecules and regulates their function, in parallel with phosphorylation of IGF-1R by Src. These findings suggest a possible involvement of RACK1 in NNK-induced activation of IGF-1R signaling via Src. On the basis of on our findings, we hypothesize that the IGF-1R and Src interact to promote the development and progression of NSCLC. In this project, we propose to: 1) assess the ability of NNK to stimulate development, growth and progression of pulmonary adenocarcinoma in mouse models with lung-specific overexpression of IGF-1R, with or without concomitant increase in Src or c-SRC tyrosine kinase (CSK) expression; 2) investigate the mechanisms and cellular roles of NNK-induced activation of IGF-1R in NSCLC cells; and 3) To determine whether inactivation of Src overrides resistance to IGF-1R-targeted therapy in mous models of NSCLC. PUBLIC HEALTH RELEVANCE: New methods for treating non-small cell lung cancer, the leading cause of cancer-related deaths in the United States, are needed. One effective strategy is to target the insulin-like growth factor (IGF) signaling axis; however, turning off the IGF axis may allow the Src pathways to continue to make the tumor grow and metastasize. We propose to study the role of the IGF axis and Src pathways in tumor growth and metastasis.

描述（由申请人提供）：需要治疗非小细胞肺癌（NSCLC）的新方法，NSCLC是美国癌症相关死亡的主要原因。通过IGF-1受体（IGF-1 R）的信号失调与癌症的发展，维持和进展有关。因此，针对NSCLC患者的一种潜在有效的治疗策略是靶向胰岛素样生长因子（IGF）信号传导轴。然而，在肺癌治疗中使用IGF-1 R靶向药物的一个潜在问题是Src家族激酶（SFK）的过表达/过度活性，其可被无数细胞刺激物激活，包括生长因子及其受体的过表达和/或突变、烟草烟雾成分、激素、整联蛋白调节的改变和粘着斑激酶的过表达。我们最近发现了Src家族激酶（SFKs）参与NSCLC中IGF-1 R激活的证据。烟草致癌物质（TC）4- 1-甲基亚硝胺（3-吡啶基）-1-丁酮（NNK）作为2-肾上腺素能受体（2-AR）和烟碱乙酰胆碱受体的激动剂，诱导NSCLC细胞系中IGF-1 R磷酸化和增殖、血管生成、侵袭活性，这些活性被SFK或2-AR抑制剂消除，但不被抗IGF-1 R单克隆抗体消除，IGF-1 R酪氨酸激酶抑制剂或nAChR拮抗剂。这些发现表明，通过涉及NNK刺激的2-AR的信号传导激活的SFKs以IGF-1 R酪氨酸激酶非依赖性方式诱导IGF-1 R磷酸化，为IGF-1 R激活提供了另一种细胞内机制，从而抵消了IGF-1 R靶向干预的抗肿瘤作用。IGF-1 R靶向药物对IGF-1 R的持续抑制诱导了c-Src的活化，进一步暗示SFKs对IGF-1 R靶向治疗具有抗性。因此，SFKs在NSCLC中的过度表达和过度活性可能是NSCLC患者使用IGF-1 R靶向药物的潜在障碍。因此，SFK靶向药物的整合可以避免对IGF-1 R靶向治疗的潜在耐药性。在我们正在进行的确定NNK诱导的IGF-1 R信号激活的机制的努力中，我们发现NNK刺激导致IGF-1 R和RACK 1的结合，RACK 1是一种结合许多信号分子并调节其功能的支架蛋白，与Src对IGF-1 R的磷酸化平行。这些发现表明RACK 1可能参与NNK诱导的IGF-1 R信号通过Src的激活。根据我们的研究结果，我们推测IGF-1 R和Src相互作用促进NSCLC的发生和发展。本研究拟：1）在肺特异性IGF-1 R过表达的小鼠模型中，评估NNK刺激肺腺癌发生、生长和进展的能力，同时观察是否伴随Src或c-SRC酪氨酸激酶（CSK）表达的增加; 2）研究NNK诱导IGF-1 R在NSCLC细胞中活化的机制和细胞作用;和3）确定Src的失活是否克服小鼠NSCLC模型对IGF-1 R靶向治疗的抗性。公共卫生相关性：需要治疗非小细胞肺癌的新方法，非小细胞肺癌是美国癌症相关死亡的主要原因。一种有效的策略是靶向胰岛素样生长因子（IGF）信号轴;然而，关闭IGF轴可能会允许Src通路继续使肿瘤生长和转移。我们建议研究IGF轴和Src通路在肿瘤生长和转移中的作用。