Elevated Epithelial Insulin-like Growth Factor Expression Is a Risk Factor for Lung Cancer Development

Kim, Woo-Young; Jin, Quanri; Oh, Sechan; Kim, Edward S.; Yang, Youngoo; Lee, Dong Hoon; Feng, Lei; Behrens, Carmen; Prudkin, Ludmila; Miller, York E.; Lee, J. Jack; Lippman, Scott M.; Hong, Waun Ki; Wistuba, Ignacio I.; Lee, Ho‐Young

doi:10.1158/0008-5472.can-08-3792

Cited by 64 publications

(83 citation statements)

References 44 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Here, we showed that the cell growth-inhibitory activity of BIIB4 and BIIB5 was also more severely compromised at elevated ligand concentrations than that of the BIIB4 and BIIB5 combination. High serum and tumor tissue IGF-I and IGF-II levels have often been observed in cancer patients, and have been associated with disease progression or prognosis (10)(11)(12)(13). Additionally, serum IGF-I levels in cancer patients were reported to increase by severalfold, in some cases exceeding 1,000 ng/mL, after treatment with IGF-IR antibodies (47).…”

Section: Discussionmentioning

confidence: 99%

“…Several strategies, such as using a monoclonal antibody (mAb), a dominant-negative mutant, or antisense oligonucleotides, all originally showed that interference of IGF-IR signaling can inhibit tumor growth in animal models (6)(7)(8). In humans, altered expression of IGF-IR, its ligands, and/or IGFBPs is frequently found in a variety of cancers (9)(10)(11)(12)(13), and elevated circulating levels of serum IGF-I are linked with increased risk of developing many cancers (14)(15)(16). In particular, IGF-II upregulation with loss of imprinting is a common event observed in several cancer types (17).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response

Dong

Demarest

Sereno

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor tyrosine kinase that mediates cell survival signaling and supports tumor progression in multiple tumor types. We identified a spectrum of inhibitory IGF-IR antibodies with diverse binding epitopes and ligand-blocking properties. By binding distinct inhibitory epitopes, two of these antibodies, BIIB4 and BIIB5, block both IGF-I and IGF-II binding to IGF-IR using competitive and allosteric mechanisms, respectively. Here, we explored the inhibitory effects of combining BIIB4 and BIIB5. In biochemical assays, the combination of BIIB4 and BIIB5 improved both the potency and extent of IGF-I and IGF-II blockade compared with either antibody alone. In tumor cells, the combination of BIIB4 and BIIB5 accelerated IGF-IR downregulation and more efficiently inhibited IGF-IR activation as well as downstream signaling, particularly AKT phosphorylation. In several carcinoma cell lines, the antibody combination more effectively inhibited ligand-driven cell growth than either BIIB4 or BIIB5 alone. Notably, the enhanced tumor growth-inhibitory activity of the BIIB4 and BIIB5 combination was much more pronounced at high ligand concentrations, where the individual antibodies exhibited substantially reduced activity. Compared with single antibodies, the BIIB4 and BIIB5 combination also significantly further enhanced the antitumor activity of the epidermal growth factor receptor inhibitor erlotinib and the mTOR inhibitor rapamycin. Moreover, in osteosarcoma and hepatocellular carcinoma xenograft models, the BIIB4 and BIIB5 combination significantly reduced tumor growth to a greater degree than each single antibody. Taken together, our results suggest that targeting multiple distinct inhibitory epitopes on IGF-IR may be a more effective strategy of affecting the IGF-IR pathway in cancer. Mol Cancer Ther; 9(9); 2593-604. ©2010 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response

Dong

Demarest

Sereno

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…IHC staining procedures were performed as described previously (10). Cytoplasmic expression was blindly analyzed and quantified by two independent pathologists (P.Y.…”

Section: Ihc Staining and Evaluation Of Tmamentioning

confidence: 99%

“…Every 20th 5-m section of the paraffin blocks (20 sections total per mouse) was evaluated after hematoxylin and eosin staining by two pathologists including one animal pathologist. Adenoma and adenocarcinoma were diagnosed according to histological criteria described previously (10).…”

Section: Histology and Ihc Of Mouse Lung Tissuesmentioning

confidence: 99%

“…The impact of the serum level of IGF-I on the risk of developing lung cancer, therefore, remains ambiguous. We have recently demonstrated that airway lung epithelial cells produce IGF (IGF-I and -II) in an autocrine manner, leading to deregulation of IGF-IR activation (10). Additionally, we showed that lung-specific overexpression of IGF-I in mouse promotes lung tumor development and progression, which is accelerated by the tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Differential Impacts of Insulin-Like Growth Factor-Binding Protein-3 (IGFBP-3) in Epithelial IGF-Induced Lung Cancer Development

Kim

Moon

et al. 2011

Endocrinology

Self Cite

View full text Add to dashboard Cite

The IGF axis has been implicated in the risk of various cancers. We previously reported a potential role of tissue-derived IGF in lung tumor formation and progression. However, the role of IGFbinding protein (IGFBP)-3, a major IGFBP, on the activity of tissue-driven IGF in lung cancer development is largely unknown. Here, we show that IGF-I, but not IGF-II, protein levels in non-small-cell lung cancer (NSCLC) were significantly higher than those in normal and hyperplastic bronchial epithelium. We found that IGF-I and IGFBP-3 levels in NSCLC tissue specimens were significantly correlated with phosphorylated IGF-IR (pIGF-IR) expression. We investigated the impact of IGFBP-3 expression on the activity of tissue-driven IGF-I in lung cancer development using mice carrying lung-specific human IGF-I transgene (Tg), a germline-null mutation of IGFBP-3, or both. . These data show that IGF-I is overexpressed in NSCLC, leading to activation of IGF-IR, and that IGFBP-3, depending on its expression level, either inhibits or potentiates IGF-I actions in lung carcinogenesis.

show abstract

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

Kim

Prudkin

Feng

et al. 2012

Cancer

Self Cite

View full text Add to dashboard Cite

Background Most patients with non–small cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We investigated the involvement of insulin-like growth factor 1 receptor (IGF-1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF-1R TKIs. Methods Phosphorylated IGF-1R/insulin receptor (pIGF-1R/IR) was immunohistochemically evaluated in a NSCLC tissue microarray. We analyzed the antitumor effects of an IGF-1R TKI (PQIP or OSI-906), either alone or in combination with a small-molecular inhibitor (PD98059 or U0126) or with siRNA targeting K-Ras or MAPK/extracellular signal-regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and EGFR or K-Ras mutations. Results pIGF-1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant (mut) K-Ras, and wild-type (wt) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF-1R TKIs exhibited significant antitumor activity in NSCLC cells with wt EGFR and wt K-Ras but not in those with mutations in these genes. Introduction of mut K-Ras attenuated the effects of IGF-1R TKIs on NSCLC cells expressing wt K-Ras. Conversely, inactivation of MEK restored sensitivity to IGF-TKIs in cells carrying mut K-Ras. Conclusions The mutation status of both EGFR and K-Ras could be predictive markers of response to IGF-1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF-1R TKIs.

show abstract

Elevated Epithelial Insulin-like Growth Factor Expression Is a Risk Factor for Lung Cancer Development

Cited by 64 publications

References 44 publications

Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response

Combination of Two Insulin-Like Growth Factor-I Receptor Inhibitory Antibodies Targeting Distinct Epitopes Leads to an Enhanced Antitumor Response

Differential Impacts of Insulin-Like Growth Factor-Binding Protein-3 (IGFBP-3) in Epithelial IGF-Induced Lung Cancer Development

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

Contact Info

Product

Resources

About