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.

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Seoul National University
Korea Rep of
Zip Code
Kim, Jin-Soo; Kim, Edward S; Liu, Diane et al. (2014) Prognostic implications of tumoral expression of insulin like growth factors 1 and 2 in patients with non-small-cell lung cancer. Clin Lung Cancer 15:213-21
Shin, Dong Hoon; Lee, Hyo-Jong; Min, Hye-Young et al. (2013) Combating resistance to anti-IGFR antibody by targeting the integrin *3-Src pathway. J Natl Cancer Inst 105:1558-70
Suh, Young-Ah; Kim, Jai-Hyun; Sung, Myung A et al. (2013) 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. Cancer Lett 332:102-9
Oh, Seung Hyun; Kang, Ju-Hee; Kyu Woo, Jong et al. (2012) A multiplicity of anti-invasive effects of farnesyl transferase inhibitor SCH66336 in human head and neck cancer. Int J Cancer 131:537-47
Kim, Jin-Soo; Kim, Edward S; Liu, Diane et al. (2012) Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer. Cancer 118:2454-65
William, W N; Kim, J-S; Liu, D D et al. (2012) The impact of phosphorylated AMP-activated protein kinase expression on lung cancer survival. Ann Oncol 23:78-85
Oh, Seung-Hyun; Kim, Woo-Young; Lee, Ok-Hee et al. (2012) Insulin-like growth factor binding protein-3 suppresses vascular endothelial growth factor expression and tumor angiogenesis in head and neck squamous cell carcinoma. Cancer Sci :
Shin, Dong Hoon; Min, Hye-Young; El-Naggar, Adel K et al. (2011) Akt/mTOR counteract the antitumor activities of cixutumumab, an anti-insulin-like growth factor I receptor monoclonal antibody. Mol Cancer Ther 10:2437-48
Kim, Woo-Young; Kim, Mi-Jung; Moon, Hojin et al. (2011) Differential impacts of insulin-like growth factor-binding protein-3 (IGFBP-3) in epithelial IGF-induced lung cancer development. Endocrinology 152:2164-73
Kim, Jai-Hyun; Choi, Dong Soon; Lee, Ok-Hee et al. (2011) Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1-mediated transcriptional events. Blood 118:2622-31

Showing the most recent 10 out of 32 publications