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: 8465096
• 负责人: HO-YOUNG LEE
• 金额: $ 16.08万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465096
• 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; receptor; receptor expression; response; small hairpin RNA; src-Family Kinases; tumor; tumor growth; tumor progression

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 ¿-adrenergic receptor (¿-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 ¿-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 ¿-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 mouse models of NSCLC.

治疗非小细胞肺癌（NSCLC）的新方法，这是癌症相关的主要原因 需要在美国死亡。通过IGF-1受体（IGF-1R）进行了放松调节的信号传导已是 与癌症的发育，维持和进展有关。因此，一种潜在的有效疗法 NSCLC患者的策略是针对胰岛素样生长因子（IGF）信号轴。一个潜力 但是，担心使用靶向IGF-1R靶向剂在肺癌治疗中的关注是 SRC家庭激酶（SFK）的过表达/多动症，可以通过无数的细胞激活 刺激，包括生长因子及其受体的过表达和/或突变，烟草成分 烟雾，激素，整联蛋白调节的改变和局灶性粘合剂激酶的过表达。我们最近 找到了SRC-家庭激酶（SFK）参与NSCLC中IGF-1R激活的证据。这 有效的烟草致癌（TC）4-（甲基硝基氨基）-1-（3-吡啶基）-1-丁酮（NNK），充当激动剂的激动剂 - 肾上腺肾上腺素受体和烟碱乙酰胆碱受体，诱导IGF-1R磷酸化和 NSCLC细胞系中的增殖剂，血管生成，侵入性活性，被SFK或SFK抑制剂废除 - AR，但不是通过抗IGF-1R单克隆抗体，IGF-1R酪氨酸激酶抑制剂或NACHR拮抗剂。 这些发现表明，通过涉及nnk刺激的信号传导激活的SFK诱导的IGF-1R 以IGF-1R酪氨酸激酶非依赖性的方式以IGF-1R的磷酸化方式，提供了替代细胞内的 IGF-1R激活的机制，从而抵消了靶向IGF-1R靶向干预的抗肿瘤作用。 通过IGF-1R靶向剂诱导C-SRC激活IGF-1R的持续抑制IGF-1R，进一步隐式SFK 抗IGF-1R靶向疗法。 NSCLC中SFK的过表达和多动症可能是 在NSCLC患者中使用IGF-1R靶向剂的潜在障碍。根据合并 针对SFK的药物可以规避对IGF-1R靶向治疗的潜在抗药性。在我们正在进行的中 确定NNK诱导的IGF-1R信号激活的机制的努力，我们发现 NNK刺激导致IGF-1R和RACK1的关联，这是一种结合多个的脚手架蛋白 信号分子并调节其功能，并与SRC磷酸化IGF-1R并行。这些 研究结果表明，RACK1可能参与NNK诱导通过SRC激活IGF-1R信号的激活。在 根据我们的发现的基础，我们假设IGF-1R和SRC相互作用以促进发展和 NSCLC的进展。在这个项目中，我们建议：1）评估NNK刺激发展的能力， 肺模型中肺腺癌的生长和进展，具有肺特异性过表达的小鼠模型 IGF-1R，SRC或C-SRC酪氨酸激酶（CSK）表达的IGF-1R； 2）调查 NNK诱导的NSCLC细胞中IGF-1R激活的机理和细胞作用； 3）确定 在NSCLC小鼠模型中，SRC的失活是否覆盖了对IGF-1R靶向疗法的抗性。

项目成果

Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1alpha.

• DOI: 10.1158/0008-5472.can-08-0505
• 发表时间: 2009-02-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Kim WY;Oh SH;Woo JK;Hong WK;Lee HY
• 通讯作者: Lee HY

A novel antitumor activity of deguelin targeting the insulin-like growth factor (IGF) receptor pathway via up-regulation of IGF-binding protein-3 expression in breast cancer.

• DOI: 10.1016/j.canlet.2013.01.022
• 发表时间: 2013-05-10
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Suh, Young-Ah;Kim, Jai-Hyun;Sung, Myung A.;Boo, Hye-Jin;Yun, Hye Jeong;Lee, Sun-Hye;Lee, Hyo-Jong;Min, Hye-Young;Suh, Young-Ger;Kim, Kyu-Won;Lee, Ho-Young
• 通讯作者: Lee, Ho-Young

A multiplicity of anti-invasive effects of farnesyl transferase inhibitor SCH66336 in human head and neck cancer.

• DOI: 10.1002/ijc.26373
• 发表时间: 2012-08-01
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Oh, Seung Hyun;Kang, Ju-Hee;Woo, Jong Kyu;Lee, Ok-Hee;Kim, Edward S.;Lee, Ho-Young
• 通讯作者: Lee, Ho-Young

Essential Role of DNA Methyltransferase 1-mediated Transcription of Insulin-like Growth Factor 2 in Resistance to Histone Deacetylase Inhibitors.

• DOI: 10.1158/1078-0432.ccr-16-0534
• 发表时间: 2017-03-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Min HY;Lee SC;Woo JK;Jung HJ;Park KH;Jeong HM;Hyun SY;Cho J;Lee W;Park JE;Kwon SJ;Lee HJ;Ni X;Shin YK;Johnson FM;Duvic M;Lee HY
• 通讯作者: Lee HY

Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors.

• DOI: 10.1002/cncr.26656
• 发表时间: 2012-08-15
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Kim WY;Prudkin L;Feng L;Kim ES;Hennessy B;Lee JS;Lee JJ;Glisson B;Lippman SM;Wistuba II;Hong WK;Lee HY
• 通讯作者: Lee HY