Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1-mediated transcriptional events

Kim, Jai-Hyun,Choi, Dong Soon,Lee, Ok-Hee,Oh, Seung-Hyun,Lippman, Scott M.,Lee, Ho-Young American Society of Hematology 2011 Blood Vol.118 No.9

<B>Abstract</B><P>Most antiangiogenic therapies currently being evaluated in clinical trials target the vascular endothelial growth factor pathway; however, the tumor vasculature can acquire resistance to vascular endothelial growth factor-targeted therapy by shifting to other angiogenesis mechanisms. Insulin-like growth factor binding protein-3 (IGFBP-3) has been reported to suppress tumor growth and angiogenesis by both IGF-dependent and IGF-independent mechanisms; however, understanding of its IGF-independent mechanisms is limited. We observed that IGFBP-3 blocked tumor angiogenesis and growth in non-small cell lung cancer and head and neck squamous cell carcinoma. Conditioned media from an IGFBP-3-treated non-small cell lung cancer cell line displayed a significantly decreased capacity to induce HUVEC proliferation and aortic sprouting. In cancer cells, IGFBP-3 directly interacted with Erk1/2, leading to inactivation of Erk1/2 and Elk-1, and suppressed transcription of early growth response protein 1 and its target genes, basic fibroblast growth factor and platelet-derived growth factor. These data suggest that IGF-independent Erk1/2 inactivation and decreased IGFBP-3-induced Egr-1 expression block the autocrine and paracrine loops of angiogenic factors in vascular endothelial and cancer cells. Together, these findings provide a molecular framework of IGFBP-3's IGF-independent antiangiogenic antitumor activities. Future studies are needed for development of IGFBP-3 as a new line of antiangiogengic cancer drug.</P>

Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer

Kim, Jin‐,Soo,Kim, Edward S.,Liu, Diane,Lee, J. Jack,Solis, Luisa,Behrens, Carmen,Lippman, Scott M.,Hong, Waun Ki,Wistuba, Ignacio I.,Lee, Ho‐,Young Wiley Subscription Services, Inc., A Wiley Company 2012 Cancer Vol.118 No.9

<P><B>Abstract</B></P><P><B>BACKGROUND:</B></P><P>The purpose of this study was to characterize insulin receptor (IR) and insulin‐like growth factor‐1 receptor (IGF‐1R) expression in patients with nonsmall cell lung cancer (NSCLC).</P><P><B>METHODS:</B></P><P>A total of 459 patients who underwent curative resection of NSCLC were studied (median follow‐up duration, 4.01 years). Expression of the IR and IGF‐1R protein in tumor specimens was assessed immunohistochemically using tissue microarrays.</P><P><B>RESULTS:</B></P><P>The cytoplasmic IR score was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC), whereas cytoplasmic IGF‐1R score was higher in patients with SCC than those with ADC. Neither IR nor IGF‐1R expression was associated with sex, smoking history, or clinical stage. Patients with positive IR or IGF‐1R expression levels had poor recurrence‐free (RFS) (3.8 vs 3.3 years; 3.8 vs 2.0 years, respectively), but similar overall survival (OS). Patients with high expression levels of IR and IGF‐1R had shorter RFS and OS compared with those with low levels of IR and/or IGF‐1R expression. Finally, a multivariate analysis revealed the impact of IR, but not of IGF‐1R, as an independent predictive marker of NSCLC survival: hazard ratio (HR) for OS, 1.005 (95% confidence interval [CI], 1.001‐1.010], HR for RFS, 1.005 (95% CI, 1.001‐1.009), when IR score was tested as a continuous variable.</P><P><B>CONCLUSIONS:</B></P><P>Overexpression of IR predicts a poor survival among patients with NSCLC, especially those with SCC. These results might serve as future guidance to the clinical trials involving IR or IGR‐1R targeting agents. Cancer 2012;. © 2011 American Cancer Society.</P>

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

Kim, Woo‐,Young,Prudkin, Ludmila,Feng, Lei,Kim, Edward S.,Hennessy, Bryan,Lee, Ju‐,Seog,Lee, J. Jack,Glisson, Bonnie,Lippman, Scott M.,Wistuba, Ignacio I.,Hong, Waun Ki,Lee, Ho‐,Youn Wiley Subscription Services, Inc., A Wiley Company 2012 Cancer Vol.118 No.16

<P><B>Abstract</B></P><P><B>BACKGROUND:</B></P><P>Most patients with nonsmall cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The authors investigated the involvement of insulinlike growth factor 1 receptor (IGF‐1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF‐1R TKIs.</P><P><B>METHODS:</B></P><P>Phosphorylated IGF‐1R/insulin receptor (pIGF‐1R/IR) was immunohistochemically evaluated in an NSCLC tissue microarray. The authors 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 <I>K‐Ras</I> or mitogen‐activated protein kinase/extracellular signal‐regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and <I>EGFR</I> or <I>K‐Ras</I> mutations.</P><P><B>RESULTS:</B></P><P>pIGF‐1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant <I>K‐Ras</I>, and wild‐type (WT) <I>EGFR</I>, 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 <I>K‐Ras</I> but not in those with mutations in these genes. Introduction of mutant <I>K‐Ras</I> attenuated the effects of IGF‐1R TKIs on NSCLC cells expressing WT <I>K‐Ras</I>. Conversely, inactivation of MEK restored sensitivity to IGF‐TKIs in cells carrying mutant <I>K‐Ras</I>.</P><P><B>CONCLUSIONS:</B></P><P>The mutation status of both <I>EGFR</I> and <I>K‐Ras</I> could be a predictive marker of response to IGF‐1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF‐1R TKIs. Cancer 2012. © 2012 American Cancer Society.</P>

Combating Resistance to Anti-IGFR Antibody by Targeting the Integrin <b>β</b>3-Src Pathway

Shin, Dong Hoon,Lee, Hyo-Jong,Min, Hye-Young,Choi, Sun Phil,Lee, Mi-Sook,Lee, Jung Weon,Johnson, Faye M.,Mehta, Kapil,Lippman, Scott M.,Glisson, Bonnie S.,Lee, Ho-Young Oxford University Press 2013 Journal of the National Cancer Institute Vol.105 No.20

<P><B>Background</B></P><P>Several phase II/III trials of anti–insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibodies (mAbs) have shown limited efficacy. The mechanisms of resistance to IGF-1R mAb-based therapies and clinically applicable strategies for overcoming drug resistance are still undefined.</P><P><B>Methods</B></P><P>IGF-1R mAb cixutumumab efficacy, alone or in combination with Src inhibitors, was evaluated in 10 human head and neck squamous cell carcinoma (HNSCC) and six non–small cell lung cancer (NSCLC) cell lines in vitro in two- or three-dimensional culture systems and in vivo in cell line– or patient-derived xenograft tumors in athymic nude mice (n = 6–9 per group). Cixutumumab-induced changes in cell signaling and IGF-1 binding to integrin β3 were determined by Western or ligand blotting, immunoprecipitation, immunofluorescence, and cell adhesion analyses and enzyme-linked immunosorbent assay. Data were analyzed by the two-sided Student <I>t</I> test or one-way analysis of variance.</P><P><B>Results</B></P><P>Integrin β3–Src signaling cascade was activated by IGF-1 in HNSCC and NSCLC cells, when IGF-1 binding to IGF-1R was hampered by cixutumumab, resulting in Akt activation and cixutumumab resistance. Targeting integrin β3 or Src enhanced antitumor activity of cixutumumab in multiple cixutumumab-resistant cell lines and patient-derived tumors in vitro and in vivo. Mean tumor volume of mice cotreated with cixutumumab and integrin β3 siRNA was 133.7mm<SUP>3</SUP> (95% confidence interval [CI] = 57.6 to 209.8mm<SUP>3</SUP>) compared with those treated with cixutumumab (1472.5mm<SUP>3</SUP>; 95% CI = 1150.7 to 1794.3mm<SUP>3</SUP>; <I>P</I> < .001) or integrin β3 siRNA (903.2mm<SUP>3</SUP>; 95% CI = 636.1 to 1170.3mm<SUP>3</SUP>; <I>P</I> < .001) alone.</P><P><B>Conclusions</B></P><P>Increased Src activation through integrin ανβ3 confers considerable resistance against anti–IGF-1R mAb-based therapies in HNSCC and NSCLC cells. Dual targeting of the IGF-1R pathway and collateral integrin β3–Src signaling module may override this resistance.</P>

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

Seung-Hyun Oh(오승현),Woo-Young Kim,Quanri Jin,Edward S. Kim,Youn Joo Yang,Dong Hoon Lee,Lei Feng,Carmen Behrens Ludmila Prudkin,York E. Miller,J. Jack Lee,Scott M. Lippman,Waun Ki Hong,Ignacio I. Wistub 한국실험동물학회 2009 한국실험동물학회 학술발표대회 논문집 Vol.2009 No.-