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)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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Seoul National University
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Min, Hye-Young; Lee, Su-Chan; Woo, Jong Kyu et al. (2017) Essential Role of DNA Methyltransferase 1-mediated Transcription of Insulin-like Growth Factor 2 in Resistance to Histone Deacetylase Inhibitors. Clin Cancer Res 23:1299-1311
Lee, S-C; Min, H-Y; Jung, H J et al. (2016) Essential role of insulin-like growth factor 2 in resistance to histone deacetylase inhibitors. Oncogene 35:5515-5526
Min, Hye-Young; Yun, Hye Jeong; Lee, Ji-Sun et al. (2015) Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer. Mol Cancer 14:113
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Kim, Jin-Soo; Kim, Edward S; Liu, Diane et al. (2015) Activation of insulin-like growth factor 1 receptor in patients with non-small cell lung cancer. Oncotarget 6:16746-56
Lee, Hyo-Jong; Lee, Ji-Sun; Hwang, Su Jung et al. (2015) Insulin-like growth factor binding protein-3 inhibits cell adhesion via suppression of integrin ?4 expression. Oncotarget 6:15150-63
Lee, Ji-Sun; Kang, Ju-Hee; Boo, Hye-Jin et al. (2015) STAT3-mediated IGF-2 secretion in the tumour microenvironment elicits innate resistance to anti-IGF-1R antibody. Nat Commun 6:8499
Jin, Quanri; Lee, Hyo-Jong; Min, Hye-Young et al. (2014) Transcriptional and posttranslational regulation of insulin-like growth factor binding protein-3 by Akt3. Carcinogenesis 35:2232-43
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

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