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）：需要在美国与癌症相关死亡的主要原因（NSCLC）治疗非小细胞肺癌（NSCLC）的新方法。通过IGF-1受体（IGF-1R）进行了放松调节的信号与癌症的发育，维持和进展有关。因此，NSCLC患者的一种潜在有效的治疗策略是针对胰岛素样生长因子（IGF）信号轴。然而，人们对使用IGF-1R靶向药物在肺癌治疗中使用的一种潜在关注是SRC-家庭激酶（SFKS）的过表达/过度活性，可以通过多种细胞刺激来激活，这些刺激是通过多种细胞刺激而激活的，包括过度表达和/或成长因子及其受体的突变，均超过表的烟雾，组成的肿块，组成了肿块，组成了整合，构成了整合构成构成的组成率，构成了构成构成构成构成构成的组成率，构成了整合构成构成构成构成的构成，构成了整合构成构成构成构成构成的构成范围。激酶。我们最近发现了SRC家庭激酶（SFK）参与NSCLC中IGF-1R激活的证据。有效的烟草致癌（TC）4-（甲基硝基氨基）-1-（3-吡啶基）-1-丁酮（NNK），充当2-肾上腺素能受体（2-AR）的激动剂（2-AR）和烟碱乙酰胆碱受体，诱导的IGF-1R活性和近距离植物植物，依次促进了IGF-1R的活性。线条被SFK或2AR的抑制剂废除，而不是由抗IGF-1R单克隆抗体，IGF-1R酪氨酸激酶抑制剂或NACHR拮抗剂所消除的。这些发现表明，通过涉及NNK刺激的2AR诱导的IGF-1R磷酸化的信号传导以IGF-1R酪氨酸激酶非依赖性的方式激活的SFK，为IGF-1R激活提供了替代的细胞内机制，从而抵消了IGF-1R抗肿瘤的抗肿瘤作用IGF-1R介入的igef-1R介入。 IGF-1R靶向剂持续抑制IGF-1R诱导C-SRC的激活，进一步暗示SFK对IGF-1R靶向的治疗的抗性。因此，NSCLC中SFK的过表达和多动症可能是NSCLC患者使用IGF-1R靶向药物的潜在障碍。因此，靶向SFK靶向药物的整合可以规避对IGF-1R靶向疗法的潜在抗药性。在我们正在进行的努力中，确定NNK诱导的IGF-1R信号激活的机制，我们发现NNK刺激导致IGF-1R和RACK1的关联，IGF-1R和RACK1是一种脚手架蛋白，该蛋白质与许多信号分子结合，并与它们的功能相结合，并与它们的磷酸化相关。这些发现表明，RACK1可能参与NNK诱导的IGF-1R信号通过SRC激活。根据我们的发现，我们假设IGF-1R和SRC相互作用以促进NSCLC的发展和发展。在该项目中，我们建议：1）评估NNK刺激IGF-1R的肺特异性过表达的小鼠模型中肺腺癌的发育，生长和进展的能力，无论SRC或CRC或不同时增加SRC或C-SRC酪氨酸激酶（CSK）的能力； 2）研究NNK诱导的NSCLC细胞中IGF-1R激活的机制和细胞作用； 3）确定在NSCLC模型中，SRC失活是否覆盖了对IGF-1R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，这是美国与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；但是，关闭IGF轴可能会使SRC途径继续使肿瘤生长和转移。我们建议研究IGF轴和SRC途径在肿瘤生长和转移中的作用。