Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The paxillin gene (PXN) encodes a focal adhesion associated protein that could be involved in the progression of lung cancer through its interactions with the actin cytoskeleton and key signal transduction oncogenes. PXN mutations and PXN amplifications were recently identified in nonsmall-cell lung cancer (NSCLC) and amplifications were associated with MET increased copy number. The description of tumors with two to three mutations in the PXN gene and the overrepresentation of GC to AT transitions were unexpected and needed confirmation. The aim of this study was to validate the incidence of PXN somatic alterations in NSCLC and to correlate them to other common genetic alterations. PXN mutations and copy number changes at PXN, EGFR, and MET loci were analyzed on DNAs from frozen tumor samples (n = 159) that had been previously screened for mutations at EGFR, KRAS, BRAF, ERBB2, STK11, PIK3CA, and TP53. We found PXN polymorphisms including nonsynonymous ones but no PXN amplification and only 1/159 (<1%) somatic tumor mutation F416L. In conclusion, we do not deny the possible involvement of PXN in cancer but our findings do not support a major role for PXN somatic changes in lung carcinogenesis.
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PMID:No somatic genetic change in the paxillin gene in nonsmall-cell lung cancer. 1935 96

Vanillin, a food flavoring agent, has been shown to suppress cancer cell migration and metastasis in a mouse model, but its mechanism of action is unknown. In this report, we have examined the antimetastatic potential of vanillin and its structurally related compounds, vanillic acid, vanillyl alcohol, and apocynin on hepatocyte growth factor (HGF)-induced migration of human lung cancer cells by the Transwell assay. Vanillin and apocynin could inhibit cell migration, and both compounds selectively inhibited Akt phosphorylation of HGF signaling, without affecting phosphorylation of Met and Erk. Vanillin and apocynin could inhibit the enzymatic activity of phosphoinositide 3-kinase (PI3K), as revealed by an in vitro lipid kinase assay, suggesting that inhibition of PI3K activity was a mechanism underlying the inhibitory effect on cancer cell migration, and the presence of an aldehyde or ketone group in the vanillin structure was important for this inhibition. Vanillin and apocynin also inhibited angiogenesis, determined by the chick chorioallantoic membrane assay.
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PMID:Vanillin suppresses metastatic potential of human cancer cells through PI3K inhibition and decreases angiogenesis in vivo. 1936 48

Aberrant proteins encoded from genes altered in tumors drive cancer development and may also be therapeutic targets. Here we derived a comprehensive gene-alteration profile of lung cancer cell lines. We tested 17 genes in a panel of 88 lung cancer cell lines and found the rates of alteration to be higher than previously thought. Nearly all cells feature inactivation at TP53 and CDKN2A or RB1, whereas BRAF, MET, ERBB2, and NRAS alterations were infrequent. A preferential accumulation of alterations among histopathological types and a mutually exclusive occurrence of alterations of CDKN2A and RB1 as well as of KRAS, epidermal growth factor receptor (EGFR), NRAS, and ERBB2 were seen. Moreover, in non-small-cell lung cancer (NSCLC), concomitant activation of signal transduction pathways known to converge in mammalian target of rapamycin (mTOR) was common. Cells with single activation of ERBB2, PTEN, or MET signaling showed greater sensitivity to cell-growth inhibition induced by erlotinib, LY294002, and PHA665752, respectively, than did cells featuring simultaneous activation of these pathways, underlining the need for combined therapeutic strategies in targeted cancer treatments. In conclusion, our gene-alteration landscape of lung cancer cell lines provides insights into how gene alterations accumulate and biological pathways interact in cancer.
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PMID:A gene-alteration profile of human lung cancer cell lines. 1947 7

Five years have passed since the activating mutation of the epidermal growth factor receptor (EGFR) gene was discovered. Patients with lung cancer harboring EGFR mutation respond remarkably well to small molecules, such as gefitinib or erlotinib, that specifically inhibit tyrosine kinase of the EGFR. Furthermore, recent evidence leads strong support to the idea that EGFR-tyrosine kinase inhibitors prolong survival of lung cancer patients with EGFR mutation. It has been also shown that secondary mutation of the EGFR gene and amplification of the MET gene are responsible for acquired resistance that emerges in virtually all cases treated with EGFR-TKI. Strategies to circumvent this resistance is currently in development. It is possible to personalize lung cancer therapy using the genetic information.
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PMID:[Small-molecule tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR)]. 1962 Jul 91

Most advanced non-small-cell lung cancers (NSCLCs) with activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or L858R) initially respond to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. However, over time (median of 6-12 months), most tumors develop acquired resistance to EGFR TKIs. Intense research in these NSCLCs has identified two major mechanisms of resistance to gefitinib/erlotinib: secondary resistance mutations and "oncogene kinase switch" systems. The secondary T790M mutation occurs in 50% of EGFR-mutated patients with TKI resistance, and in vitro, this mutation negates the hypersensitivity of activating EGFR mutations. Sensitive detection methods have identified a proportion of TKI-naive tumors that carry T790M, and these resistant clones may be selected after exposure to gefitinib or erlotinib. Other secondary resistance mutations (D761Y, L747S, T854A) seem to be rare. The amplification of the MET oncogene is present in 20% of TKI-resistant tumors; however, in half of the cases with this "oncogene kinase switch" mechanism the T790M is coexistent. It is possible that other kinases (such as insulin-like growth factor-1 receptor [IGF-1R]) might also be selected to bypass EGFR pathways in resistant tumors. The growing preclinical data in EGFR-mutated NSCLCs with acquired resistance to gefitinib or erlotinib has spawned the initiation or conception of clinical trials testing novel EGFR inhibitors that in vitro inhibit T790M (neratinib, XL647, BIBW 2992, and PF-00299804), MET, or IGF-1R inhibitors in combination with EGFR TKIs, and heat shock protein 90 inhibitors. Ongoing preclinical and clinical research in EGFR-mutated NSCLC has the potential to significantly improve the outcomes of patients with these somatic mutations.
Clin Lung Cancer 2009 Jul
PMID:Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. 1963 48

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib and erlotinib, are reversible competitive inhibitors of the tyrosine kinase domain of EGFR that bind to its adenosine-5' triphosphate-binding site. Somatic activating mutations of the EGFR gene, increased gene copy number and certain clinical and pathological features have been associated with dramatic tumor responses and favorable clinical outcomes with these agents in patients with non-small-cell lung cancer (NSCLC). The specific types of activating mutations that confer sensitivity to EGFR TKIs are present in the tyrosine kinase (TK) domain of the EGFR gene. Exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21 are the most frequent in NSCLC and are termed 'classical' mutations. The NSCLC tumors insensitive to EGFR TKIs include those driven by the KRAS and MET oncogenes. Most patients who initially respond to gefitinib and erlotinib eventually become resistant and experience progressive disease. The point mutation T790M accounts for about one half of these cases of acquired resistance. Various second-generation EGFR TKIs are currently being evaluated and may have the potential to overcome T790M-mediated resistance by virtue of their irreversible inhibition of the receptor TK domain.
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PMID:Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. 1968 Feb 93

The development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) seems almost inevitable, even in patients with lung cancer that initially respond well to EGFR-TKIs. MET amplification was recently found to be a mechanism of escape from the anticancer effect of EGFR inhibitors. In the present study, we investigated the means whereby MET affects sensitivity to EGFR-TKIs in PC-9 cells. Gefitinib- or erlotinib-resistant sublines were established by exposing the parental PC-9 cell line to chronic, repeated treatments with these drugs. These resistant sublines showed more than 100-fold more resistance to gefitinib and erlotinib and acquired cross-resistance to other EGFR-TKIs. The T790M EGFR mutation was found by pyrosequencing, and this seemed to be the cause of drug resistance. Resistant cells also showed MET activation, although gene amplification was not detected. Furthermore, the induction of MET activity was not found to be associated with sensitivity to EGFR-TKIs. Interestingly, increased passage number without exposure to gefitinib or erlotinib caused MET activation, but this did not affect sensitivity to EGFR-TKIs. In addition, hepatocyte growth factor was found to block the ability of EGFR-TKIs to inhibit MET activation. However, sustained MET activation by hepatocyte growth factor did not modulate the cellular effects of gefitinib or erlotinib. Rather, activated MET enhanced migration and invasion abilities. Summarizing, MET activation may be acquired during cancer cell proliferation and enhances migratory and invasive abilities without affecting cellular sensitivity to EGFR-TKIs. Accordingly, the present study suggests that MET activation caused by factors other than MET gene amplification is not a suitable surrogate marker of resistance to EGFR-TKIs.
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PMID:The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors. 1980 4

The nonsteroidal anti-inflammatory drug (NSAID), tolfenamic acid (TA) is emerging as a new anti-cancer agent. TA induces the degradation of specific Specificity protein (Sp) transcription factors, Sp1, Sp3 and Sp4 which are associated with tumor growth and metastasis. In this study we have evaluated the effect of TA on lung cancer using both in vitro and in vivo models. TA in a dose dependent manner inhibited proliferation and cell viability of two different lung cancer cells, A549 and CRL5803. TA treatment for 48 h significantly decreased the expression of Sp1, Sp3 and Sp4. The hepatocyte growth factor receptor, c-Met is overexpressed in a variety of cancers including lung cancer and Sp proteins mediate the regulation of c-Met. TA diminished the expression of c-Met protein and modulates its downstream signaling pathway. Furthermore, TA treatment significantly increased the number of apoptotic cells and pro-apoptotic markers c-PARP and Bax confirming the activation of apoptotic pathways. In vivo studies using the orthotopic mice model for lung cancer showed that TA (25 mg/kg/2 days and 50 mg/kg/2 days) resulted in a dose dependent decrease in tumor formation. The immunohistochemical staining of lung tissue showed high expression of Sp1, Sp3, Sp4, c-Met and phospho Met in control group and a dose dependent decrease in TA treated groups. The crucial findings of this study support that targeting c-Met with a potent inhibitor of Sp proteins is a robust strategy for the implications in lung cancer treatment and TA can serve as a therapeutic agent for this devastating disease.
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PMID:Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice. 1985 11

Lung cancer is the most common tumor-related cause of death in western industrialized countries, despite continuous improvement in both diagnostic and therapeutic approaches. Since epidermal growth factor receptor (EGFR) is overexpressed in 80% of cases of non-small cell lung carcinoma, mediating important carcinogenic properties such as cell-cycle progression, apoptosis, angiogenesis and metastasis, it is considered a relevant target in novel specific therapies. This has lead to the development of the low-molecular EGFR tyrosine kinase inhibitors (EGFR-TKI) Gefitinib and Erlotinib. Predicting which patients will respond to an EGFR-targeted therapy is of particular clinical interest. Recent studies show a significantly better response and prolonged progression-free survival in patients with EGFR-mutated tumors, even when used as first-line therapy. Moreover, genetic mutations which correlate to primary EGFR-TKI resistance (e.g. KRAS) or produce secondary resistance to known TKI (e.g. EGFR mutation T790 M or MET amplification) have meanwhile been explained. Predictive diagnosis of these mutations using histological material is becoming increasingly important for patient stratification and will soon be indispensable not only for lung cancer.
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PMID:[Molecular diagnostics in lung carcinoma for therapy stratification]. 1999 36

Seventy-five percent of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations respond to treatment with the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib; however, drug-resistant tumors eventually emerge. In 60% of cases, resistant tumors carry a secondary mutation in EGFR (T790M), amplification of MET, or both. Here, we describe the establishment of erlotinib resistance in lung tumors, which were induced by mutant EGFR, in transgenic mice after multiple cycles of drug treatment; we detect the T790M mutation in five out of 24 tumors or Met amplification in one out of 11 tumors in these mice. This preclinical mouse model, therefore, recapitulates the molecular changes responsible for resistance to TKIs in human tumors and holds promise for the discovery of additional mechanisms of drug resistance in lung cancer.
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PMID:Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma. 2000 86


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