Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The receptors erbB-3 and erbB-4 are members of the type 1 tyrosine kinase receptor family which also comprises epidermal growth factor receptor (EGF-R) and erbB-2. ErbB-3 and erbB-4 receptors are known to bind a family of related proteins termed heregulins. In this study, we report differential expression of P185erbB-2, P160erbB-3 and P180erbB-4, and their ligand heregulin alpha, in normal bronchial epithelial, and non-small cell lung carcinoma (NSCLC) cell lines. Expression of P185erbB-2 and P160erbB-3 vary from very low to a high level in NSCLC cell lines and a low level in normal bronchial cells. In contrast, P180erbB-4 was detected only in NSCLC cell lines but not in normal bronchial cells. Heregulin alpha is expressed at intermediate levels in the normal and cancer cell lines studied. Immunoprecipitation, using antibodies to erbB-2, erbB-3 or erbB-4 receptors, coupled to phosphotyrosine Western blot analysis indicates that these three receptors are constitutively tyrosine phosphorylated in lung cancer cell lines, but only erbB-2 and erbB-3 are autophosphorylated in normal cells. These data suggest that constitutive activation of erbB-2, erbB-3 and erbB-4 receptors could be induced by heregulin alpha via an autocrine loop mechanism, and that the active forms of erbB-4 may cooperate with the other members of the EGF-receptor family in human lung carcinogenesis.
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PMID:Expression of P185erbB-2, P160erbB-3, P180erbB-4, and heregulin alpha in human normal bronchial epithelial and lung cancer cell lines. 1022 86

Lung cancer, like many other epithelial malignancies, is thought to be the outcome of genetic and epigenetic changes that result in a constellation of phenotypic abnormalities in bronchial epithelium. These include morphologic epithelial dysplasia, angiogenesis, increased proliferative rate, and changes in expression of cell surface proteins, particularly overexpression of epidermal growth factor receptor (EGFR) family proteins. The EFGR family is a group of four structurally similar tyrosine kinases (EGFR, HER2/neu, ErbB-3, and ErbB-4) that dimerize on binding with a number of ligands, including EGF and transforming growth factor alpha. Epidermal growth factor receptor overexpression is pronounced in virtually all squamous carcinomas and is also found in > or = 65% of large cell and adenocarcinomas. It is not expressed in situ by small cell lung carcinoma. Overexpression of EGFR is one of the earliest and most consistent abnormalities in bronchial epithelium of high-risk smokers. It is present at the stage of basal cell hyperplasia and persists through squamous metaplasia, dysplasia, and carcinoma in situ. Recent studies of the effect of inhibitors of receptor tyrosine kinases suggest that patterns of coexpression of multiple members of the EGFR family could be important in determining response. Intermediate endpoints of such trials could include monitoring of phosphorylation levels in signal transduction molecules downstream of the receptor dimers. These trials represent a new targeted approach to lung cancer treatment and chemoprevention that will require greater attention to molecular endpoints than required in past trials.
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PMID:Epidermal growth factor receptor family in lung cancer and premalignancy. 1189 9

We previously demonstrated that a ligand-blocking monoclonal antibody (mAb) against the epidermal growth factor-receptor (EGF-R), LA1, induced morphological conversion from epithelial-like to epithelial of the human lung cancer cell line, H322. This was accompanied by an up-regulation of epithelial cadherin (E-cadherin) expression (Clin. Cancer Res. 5 (1999) 681). In the present paper, we show that mAb LA1 induces the epithelial-like to epithelial conversion of the human lung cancer cell line, A549. In A549 and H322 cells, which express a detectable amount of EGF-R (ErbB-1), ErbB-2, ErbB-3, and ErbB-4 receptors, the LA1 mAb induces up-regulation of the E-cadherin/catenin complex (alpha-, beta-, and gamma-catenins). This is associated with re-localization of E-cadherin, alpha-catenin, (and to a lesser extent beta-catenin), but not gamma-catenin. Additionally, we report that mAb LA1 inhibits cell motility. In contrast, epidermal growth factor (EGF) or heparin-binding EGF-like growth factor (HB-EGF) induces the epithelial-like to fibroblastoid conversion of A549 and H322 cell lines, slightly reduces the expression of E-cadherin and beta-catenin, but not alpha- and gamma-catenins, and stimulates cell motility. These studies demonstrate that EGF-R modulation regulates the E-cadherin/catenin complex and cell motility in human lung epithelial carcinoma cells. Our results may have important therapeutic implications for the treatment of invasive human lung carcinomas via the restoration of the cadherin/catenin complex using inhibitors of EGF-R.
Lung Cancer 2002 Jul
PMID:Regulation of E-cadherin/catenin complex patterns by epidermal growth factor receptor modulation in human lung cancer cells. 1205 67

EGFR is frequently mutated and amplified in lung adenocarcinomas sensitive to EGFR inhibitors gefitinib and erlotinib. A secondary mutation, T790M, has been associated with acquired resistance but has not been shown to be sufficient to render EGFR mutant/amplified lung cancers resistant to EGFR inhibitors. We created a model for studying acquired resistance to gefitinib by prolonged exposure of a gefitinib-sensitive lung carcinoma cell line (H3255; EGFR mutated and amplified) to gefitinib in vitro. The resulting resistant cell line acquired a T790M mutation in a small fraction of the amplified alleles that was undetected by direct sequencing and identified only by a highly sensitive HPLC-based technique. In gefitinib-sensitive lung cancer cells with EGFR mutations and amplifications, exogenous introduction of EGFR T790M effectively conferred resistance to gefitinib and continued ErbB-3/PI3K/Akt signaling when in cis to an activating mutation. Moreover, continued activation of PI3K signaling by the PIK3CA oncogenic mutant, p110alpha E545K, was sufficient to abrogate gefitinib-induced apoptosis. These findings suggest that allelic dilution of biologically significant resistance mutations may go undetected by direct sequencing in cancers with amplified oncogenes and that restoration of PI3K activation via either a T790M mutation or other mechanisms can provide resistance to gefitinib.
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PMID:Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. 1690 27

EGFR mutation-induced drug resistance has become a major threat to the treatment of non-small-cell lung carcinoma. Essentially, the resistance mechanism involves modifications of the intracellular signaling pathways. In our work, we separately investigated the EGFR and ErbB-3 heterodimerization, regarded as the origin of intracellular signaling pathways. On one hand, we combined the molecular interaction in EGFR heterodimerization with that between the EGFR tyrosine kinase and its inhibitor. For 168 clinical subjects, we characterized their corresponding EGFR mutations using molecular interactions, with three potential dimerization partners (ErbB-2, IGF-1R and c-Met) of EGFR and two of its small molecule inhibitors (gefitinib and erlotinib). Based on molecular dynamics simulations and structural analysis, we modeled these mutant-partner or mutant-inhibitor interactions using binding free energy and its components. As a consequence, the mutant-partner interactions are amplified for mutants L858R and L858R_T790M, compared to the wild type EGFR. Mutant delL747_P753insS represents the largest difference between the mutant-IGF-1R interaction and the mutant-inhibitor interaction, which explains the shorter progression-free survival of an inhibitor to this mutant type. Besides, feature sets including different energy components were constructed, and efficient regression trees were applied to map these features to the progression-free survival of an inhibitor. On the other hand, we comparably examined the interactions between ErbB-3 and its partners (EGFR mutants, IGF-1R, ErbB-2 and c-Met). Compared to others, c-Met shows a remarkably-strong binding with ErbB-3, implying its significant role in regulating ErbB-3 signaling. Moreover, EGFR mutants corresponding to poor clinical outcomes, such as L858R_T790M, possess lower binding affinities with ErbB-3 than c-Met does. This may promote the communication between ErbB-3 and c-Met in these cancer cells. The analysis verified the important contribution of IGF-1R or c-Met in the drug resistance mechanism developed in lung cancer treatments, which may bring many benefits to specialized therapy design and innovative drug discovery.
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PMID:Contribution of EGFR and ErbB-3 Heterodimerization to the EGFR Mutation-Induced Gefitinib- and Erlotinib-Resistance in Non-Small-Cell Lung Carcinoma Treatments. 2599 17