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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the major role of the AKT/PKB family of proteins in the regulation of many growth and survival mechanisms in the cell, and the increasing evidence suggesting that AKT disruption could play a key role in many human malignancies, no major mutations of AKT genes had been reported, until very recently when Carpten et al reported a novel transforming mutation (E17K) in the pleckstrin homology domain of the AKT1 gene in solid tumours. Several laboratories are now screening for this mutation in different malignancies, and, recently, the mutation was described by Malanga et al in 1.9% of lung cancer patients. Considering the importance of the PI3K/AKT pathway in mediating survival and antiapoptotic signals in the B-cell types of chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL), we sequenced the AKT1 exon 3 for the above mentioned mutation in 87 specimens, representing 45 CLLs, 38 ALLs and 4 prolymphocytic leukaemia (PLL) cases, which are all of B-cell origin. Our results show that the mutation E17K/AKT1 was not detected in the pleckstrin homology domain of AKT1 of the investigated cases. We conclude that this mutation is not a major event in B-cell-derived lymphoid leukaemias.
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PMID:The transforming mutation E17K/AKT1 is not a major event in B-cell-derived lymphoid leukaemias. 1866 77

Common genetic variation may play an important role in altering lung cancer risk. We conducted a pathway-based candidate gene evaluation to identify genetic variations that may be associated with lung cancer in a population-based case-control study in Xuan Wei, China (122 cases and 111 controls). A total of 1260 single-nucleotide polymorphisms (SNPs) in 380 candidate genes for lung cancer were successfully genotyped and assigned to one of 10 pathways based on gene ontology. Logistic regression was used to assess the marginal effect of each SNP on lung cancer susceptibility. The minP test was used to identify statistically significant associations at the gene level. Important pathways were identified using a test of proportions and the rank truncated product methods. The cell cycle pathway was found as the most important pathway (P = 0.044) with four genes significantly associated with lung cancer (PLA2G6 minP = 0.001, CCNA2 minP = 0.006, GSK3 beta minP = 0.007 and EGF minP = 0.013), after adjusting for multiple comparisons. Interestingly, most cell cycle genes that were associated with lung cancer in this analysis were concentrated in the AKT signaling pathway, which is essential for regulation of cell cycle progression and cellular survival, and may be important in lung cancer etiology in Xuan Wei. These results should be viewed as exploratory until they are replicated in a larger study.
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PMID:Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway. 1867 80

Resistance to chemotherapy in cancer is common. As gene expression profiling has been shown to anticipate chemotherapeutic resistance, we sought to identify cellular pathways associated with resistance to facilitate effective combination therapy. Gene set enrichment analysis was used to associate pathways with resistance in two data sets: the NCI-60 cancer cell lines deemed sensitive and resistant to specific chemotherapeutic agents (Adriamycin, cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, paclitaxel, and topotecan) and a series of 40 lung cancer cell lines for which sensitivity to cisplatin and docetaxel was determined. Candidate pathways were further screened in silico using the Connectivity Map. The lead candidate pathway was functionally validated in vitro. Gene set enrichment analysis associated the matrix metalloproteinase, p53, methionine metabolism, and free pathways with cytotoxic resistance in the NCI-60 cell lines across multiple agents, but no gene set was common to all drugs. Analysis of the lung cancer cell lines identified the bcl-2 pathway to be associated with cisplatin resistance and the AKT pathway enriched in cisplatin- and docetaxel-resistant cell lines. Results from Connectivity Map supported an association between phosphatidylinositol 3-kinase/AKT and docetaxel resistance but did not support the association with cisplatin. Targeted inhibition of the phosphatidylinositol 3-kinase/AKT pathway with LY294002, in combination with docetaxel, resulted in a synergistic effect in previously docetaxel-resistant cell lines but not with cisplatin. These results support the use of a genomic approach to identify drug-specific targets associated with the development of chemotherapy resistance and underscore the importance of disease context in identifying these pathways.
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PMID:A genomic approach to identify molecular pathways associated with chemotherapy resistance. 2246 60

Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) exhibits potent carcinogenic activity in vitro and in vivo and has been shown to contribute to multiple steps in the tumorigenesis of lung cancer. In this study, we found that NNK up-regulated the expression of contactin-1, a cell adhesion molecule which has been implicated in cell migration, in lowly invasive CL1.0 lung cancer cells in a dose-dependent manner. Reverse transcription-polymerase chain reaction (RT-PCR) analysis and promoter activity assay suggested that NNK directly stimulated contactin-1 gene transcription. Block of alpha7 nicotinic acetylcholine receptor (nAChR) by alpha-bungarotoxin attenuated NNK-induced increase of contactin-1. We also found that NNK activated alpha7 nAChR downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways in CL1.0 cells. However, only ERK signaling pathway inhibitor PD98059, but not AKT signaling pathway inhibitor LY294002, suppressed the induction of contactin-1 by NNK. Up-regulation of contactin-1 by NNK increased adhesive and invasive abilities of CL1.0 cells which could be effectively inhibited by contactin-1 neutralizing antibody, alpha-bungarotoxin and PD98059. Taken together, we conclude that contactin-1 is a molecule mediator for NNK to promote invasiveness of lung cancer cells.
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PMID:4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) enhances invasiveness of lung cancer cells by up-regulating contactin-1 via the alpha7 nicotinic acetylcholine receptor/ERK signaling pathway. 1902 25

EGFR (ErbB1) and ErbB2 receptors stimulate several intracellular signaling pathways in non-small-cell lung cancer (NSCLC). Adenocarcinomas (AC) and squamous cell carcinomas (SCC) are NSCLC subtypes with distinct clinico-pathological features, and responses to ErbB-targeted inhibitors treatment. To evaluate the causes of these differences, tissue microarrays with samples from NSCLC patients (189 AC and 56 SCC) were used to study EGFR and ErbB2 expression and phospho-activation of ERK1/2, AKT, STAT3 and SRC ErbB-mediators by immunohistochemistry and Western blot, and EGFR and ErbB2 gene amplification by FISH. EGFR expression was higher in SCC than in AC (P<0.001), while ErbB2 showed similar low levels. Phosphorylated (p) ERK, pAKT, pSTAT3 and pSRC levels were prevalent in AC (P< or =0.002). EGFR levels and signaling mediators activation were differentially associated with each of the pathologies. Whereas in AC the expression and amplification of EGFR were linked to AKT activation (P< or =0.050), in SCC its expression was correlated with pSTAT3 (P=0.024). In addition, pSTAT3 was correlated with pERK and pAKT only in AC (P< or =0.045). Biomarker levels were also differentially associated with the clinico-pathologic variables. In AC, EGFR and pSRC increasing scores correlated with female sex and the smoking habit (P< or =0.008), while ErbB2 amplification increased with advanced age and tumor stage (P< or =0.047), and pERK1/2 and pSTAT3 levels correlated with early tumor stage (P< or =0.045). In SCC, EGFR amplification was stronger in younger patients (P=0.013), pERK1/2 in the older ones (P=0.050), and pSTAT3 amplification was stronger in women (P=0.001). These data support that AC and SCC lung tumors are distinct entities at the molecular level, and that their signaling status in combination with their clinico-pathologic variables may be considered for differential targeted therapies.
Lung Cancer 2009 Jul
PMID:Differential ErbB receptor expression and intracellular signaling activity in lung adenocarcinomas and squamous cell carcinomas. 1904 92

The validation of predictive biomarkers to tailor chemotherapy is a key issue in the development of effective treatment modalities against cancer. Examples of how genetics might affect drug response are offered by gemcitabine. A substantial number of potential biomarkers for sensitivity or resistance to gemcitabine have been proposed, including ribonucleotide reductase and cytidine deaminase polymorphisms, human equilibrative transporter-1 and ribonucleotide reductase gene-expression and AKT phosphorylation status. These markers displayed a significant relationship with disease response to the drug; however, their robustness needs to be evaluated within prospective studies. Moreover, recent trials of customized chemotherapy based on genetic markers have been carried out in non-small-cell lung cancer and promising pharmacogenetic determinants are gaining momentum, including BRCA1 and ERCC1. Hopefully, biomarkers to select patients most likely to respond to gemcitabine will be validated in the near future.
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PMID:Pharmacogenomics of gemcitabine in non-small-cell lung cancer and other solid tumors. 1910 17

SEMA3F is a secreted semaphorin with potent antitumor activity, which is frequently downregulated in lung cancer. In cancer cell lines, SEMA3F overexpression decreases hypoxia-induced factor 1alpha protein and vascular endothelial growth factor mRNA, and inhibits multiple signaling components. Therefore, understanding how SEMA3F expression is inhibited in cancer cells is important. We previously defined the promoter organization of SEMA3F and found that chromatin remodeling by a histone deacetylase inhibitor was sufficient to activate SEMA3F expression. In lung cancer, we have also shown that ZEB-1, an E-box transcription repressor, is predominantly responsible for loss of E-Cadherin associated with a poor prognosis and resistance to epidermal growth factor receptor inhibitors. In the present study, we demonstrated that ZEB-1 also inhibits SEMA3F in lung cancer cells. Levels of ZEB-1, but not ZEB-2, Snail or Slug, significantly correlate with SEMA3F inhibition, and overexpression or inhibition of ZEB-1 correspondingly affected SEMA3F expression. Four conserved E-box sites were identified in the SEMA3F gene. Direct ZEB-1 binding was confirmed by chromatin immunoprecipitation assays for two of these, and ZEB-1 binding was reduced when cells were treated with a histone deacetylase inhibitor. These results demonstrate that ZEB-1 directly inhibits SEMA3F expression in lung cancer cells. SEMA3F loss was associated with changes in cell signaling: increased phospho-AKT in normoxia and increase of hypoxia-induced factor 1alpha protein in hypoxia. Moreover, exogenous addition of SEMA3F could modulate ZEB-1-induced angiogenesis in a chorioallantoic membrane assay. Together, these data provide further support for the importance of SEMA3F and ZEB-1 in lung cancer progression.
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PMID:ZEB-1, a repressor of the semaphorin 3F tumor suppressor gene in lung cancer cells. 1917

Lung cancer is one of the most prevalent cancers worldwide. This study focused on small cell lung cancer (SCLC), which has a poor clinical prognosis, and attempted to elucidate potential therapeutic molecular targets. A target-specific mutational search revealed mutation of the PIK3CA gene in three of 13 SCLC cell lines and two of 15 primary SCLCs. By introducing these mutant PIK3CA cDNAs, we established artificial "PIK3CA-addicted" cells and found that Tricribine, a small-molecule inhibitor of AKT signaling that is located downstream from PIK3CA, significantly inhibited the growth and colony formation activity of these cells. Using cancer cell lines, we further showed that PIK3CA-mutated SCLC cells are more sensitive to Tricribine than PIK3CA wild-type cells. Additionally, we found that a cisplatin-resistant subclone of PIK3CA-mutant SCLC cells was equally sensitive to Tricribine. This study for the first time uncovered PIK3CA alterations in SCLC, and our findings suggest that anti-AKT molecular therapy could be effective for a subgroup of SCLC, which shows activation of specific genes, such as PIK3CA mutation, and that genetic stratification of SCLC according to the activation status of individual therapeutic target pathways could be clinically beneficial, especially for chemotherapy-resistant/relapsing tumors.
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PMID:Oncogenic mutation of PIK3CA in small cell lung carcinoma: a potential therapeutic target pathway for chemotherapy-resistant lung cancer. 1939 61

GLI family members are zinc-finger transcription factors, which are involved in embryogenesis and carcinogenesis through transcription regulation of GLI1, CCND1, CCND2, FOXA2, FOXC2, RUNX2, SFRP1, and JAG2. GLI1 transcription is upregulated in a variety of human tumors, such as basal cell carcinoma, lung cancer, breast cancer, gastric cancer, pancreatic cancer, and esophageal cancer. Hedgehog signaling via Smoothened cascade and receptor tyrosine kinase (RTK) signaling via PI3K-AKT cascade induce stabilization of GLI1 protein, whereas G-protein coupled receptor (GPCR) signaling via Gs-PKA cascade induces degradation of GLI1 protein. Here we report integrative genomic analyses of the GLI1 gene. The GLI1 and ARHGAP9 genes are located in a tail-to-tail manner with overlapping 3'-ends. ARHGAP9 was expressed in bone marrow, spleen, thymus, monocytes, and macrophages, whereas GLI1 was almost undetectable in normal tissues or cells with predominant ARHGAP9 expression. Because overlapping sense and anti-sense transcripts are annealed to each other to give rise to double-stranded RNAs functioning as endogenous RNAi, GLI1 expression might be negatively regulated by ARHGAP9 transcripts. GLI-binding element with one base substitution at the +1589-bp position from the transcriptional start site (TSS) of the human GLI1 gene was completely conserved in chimpanzee GLI1, mouse Gli1, and rat Gli1 genes. Ten Smad-binding elements, double E-boxes for EMT regulators, and double N-boxes for HES/HEY family members within intron 1 of the human GLI1 gene were also conserved in mammalian GLI1 orthologs. GLI1 transcription is upregulated due to Hedgehog, and TGFbeta signaling activation, whereas GLI1 transcription is downregulated due to Snail/Slug, and Notch signaling activation. Together these facts indicate that Hedgehog, TGFbeta, and RTK signals positively regulate GLI1, and that Notch, and GsPCR signals negatively regulate the GLI1.
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PMID:Integrative genomic analyses on GLI1: positive regulation of GLI1 by Hedgehog-GLI, TGFbeta-Smads, and RTK-PI3K-AKT signals, and negative regulation of GLI1 by Notch-CSL-HES/HEY, and GPCR-Gs-PKA signals. 1951 67

In recent years no cancer therapeutic class has undergone more prolific or successful drug development efforts than the kinase inhibitors. The robust research interest is evident in the number of kinase inhibitor presentations at the American Association for Cancer Research Annual Meeting held in Denver (CO, USA) 18-22 April 2009. Presentation highlights from the Kinase Inhibitor 4 Minisymposium include the identification of FGF receptor genetic alterations that correlate with sensitivity to the kinase inhibitor TKI258; evaluation of activity of mitotic kinase inhibitors GSK461364A and AZD1152 in breast and small-cell lung cancer and the identification of new inhibitors to PI3K/AKT/mTOR pathway.
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PMID:Kinase Inhibitor 4 Minisymposium summary. 1958 28


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