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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>
Kim, Seung-Wook,Cheon, Kyounga,Kim, Chang-Hoon,Yoon, Joo-Heon,Hawke, David H.,Kobayashi, Ryuji,Prudkin, Ludmila,Wistuba, Ignacio I.,Lotan, Reuben,Hong, Waun Ki,Koo, Ja Seok American Association for Cancer Research 2007 Cancer Research Vol.67 No.14
<P>Squamous cell carcinoma in the lung originates from bronchial epithelial cells that acquire increasingly abnormal phenotypes. Currently, no known biomarkers are clinically efficient for the early detection of premalignant lesions and lung cancer. We sought to identify secreted molecules produced from squamous bronchial epithelial cells cultured with organotypic culture methods. We analyzed protein expression patterns in the apical surface fluid (ASF) from aberrantly differentiated squamous metaplastic normal human tracheobronchial epithelial (NHTBE) and mucous NHTBE cells. Comparative two-dimensional PAGE analysis revealed 174 unique proteins in the ASF of squamous NHTBE cells compared with normal mucociliary differentiated NHTBE cells. Among them, 64 well-separated protein spots were identified by liquid chromatography-tandem mass spectrometry, revealing 22 different proteins in the ASF from squamous NHTBE cells. Expression of six of these proteins [SCC antigen 1 (SCCA1), SCC antigen 2 (SCCA2), S100A8, S100A9, Annexin I, and Annexin II] in the squamous NHTBE cells was further confirmed with immunoblot analysis. Notably, SCCA1 and SCCA2 were verified as being expressed in squamous metaplastic NHTBE cells but not in normal mucous NHTBE or normal bronchial epithelium. Moreover, SCCA1 and SCCA2 expression increased in in vitro lung carcinogenesis model cell lines with increasing malignancy. In summary, we identified proteins that are uniquely secreted from squamous metaplastic primary human bronchial epithelial cells cultured by the organotypic air-liquid interface method. These ASF proteins may be used to detect abnormal lesions in the lung without collecting invasive biopsy specimens.</P>