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，与癌症相关的主要原因

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

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

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

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

表皮生长因子受体和K-RAS突变以及肺癌对胰岛素样生长因子1受体酪氨酸激酶抑制剂的耐药性。

• 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