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

Development of acquired resistance to gefitinib after an initial good response is common. Recently, it was reported that this acquired resistance is related to a secondary mutation associated with a substitution of threonine by methionine at codon 790 (T790M) of the epidermal growth factor receptor (EGFR) gene. In this report, we present a "never smoking" woman with advanced lung cancer who showed acquired resistance to gefitinib, and analysis of autopsy samples revealed no evidence of EGFR mutations in either exons 18-21 or codon 790, and positive immunostaining for breast cancer resistance protein (BCRP). We describe, for the first time, a case in which expression of BCRP was associated with acquired resistance to gefitinib, independent of EGFR mutations.
Lung Cancer 2007 Nov
PMID:Breast cancer resistance protein (BCRP) affected acquired resistance to gefitinib in a "never-smoked" female patient with advanced non-small cell lung cancer. 1761 5

Recently, we identified a lung adenocarcinoma signature that segregated tumors into three clades distinguished by histological invasiveness. Among the genes differentially expressed was the type II transforming growth factor-beta receptor (TGFbetaRII), which was lower in adenocarcinoma mixed subtype and solid invasive subtype tumors compared with bronchioloalveolar carcinoma. We used a tumor cell invasion system to identify the chemokine CCL5 (RANTES, regulated on activation, normal T-cell expressed and presumably secreted) as a potential downstream mediator of TGF-beta signaling important for lung adenocarcinoma invasion. We specifically hypothesized that RANTES is required for lung cancer invasion and progression in TGFbetaRII-repressed cells. We examined invasion in TGFbetaRII-deficient cells treated with two inhibitors of RANTES activity, Met-RANTES and a CCR5 receptor-blocking antibody. Both treatments blocked invasion induced by TGFbetaRII knockdown. In addition, we examined the clinical relevance of the RANTES-CCR5 pathway by establishing an association of RANTES and CCR5 immunostaining with invasion and outcome in human lung adenocarcinoma specimens. Moderate or high expression of both RANTES and CCR5 was associated with an increased risk for death, P=0.014 and 0.002, respectively. In conclusion, our studies indicate RANTES signaling is required for invasion in TGFbetaRII-deficient cells and suggest a role for CCR5 inhibition in lung adenocarcinoma prevention and treatment.
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PMID:Lung adenocarcinoma invasion in TGFbetaRII-deficient cells is mediated by CCL5/RANTES. 1765 92

Increasing knowledge regarding multiple genetic disturbances found in human lung cancers, particularly non-small cell lung cancer (NSCLC), have enabled predictive markers to be used in specialised centres in tailoring chemotherapy regimens and improving survival and response in subgroups of patients. Impressive responses are observed in patients with epidermal growth factor receptor (EGFR) tyrosine kinase mutations following treatment with gefitinib and erlotinib; and methylation of the mitotic checkpoint gene 14-3-3sigma in circulating tumour serum DNA predicts response to cisplatin/gemcitabine therapy. Expression of markers of DNA repair, ERCC1, RRM1 and BRCA1 are also determinants of response to cisplatin/gemcitabine, with low levels of mRNA predicting improved survival. Patients harbouring the Met/Met mutation in XRCC3 240 have significantly better survival compared with other mutations. These findings are presented in this article, as well as their relevance in customising chemotherapy - illustrated by a hypothetical model guiding treatment decisions in the management of NSCLC.
Lung Cancer 2007 Aug
PMID:How could pharmacogenomics help improve patient survival? 1768 45

Many asbestos-like mineral fibers have been detected in the air of mountainous and volcanic areas of Italy and other parts of the world. These fibers have been suspected to be the cause of increased incidences of lung cancer and other lung diseases in these areas. However, the mechanisms of the cellular response and defense following exposure to these microscopic fibers have not been characterized. We continue to study these mechanisms to be able to propose preventive strategies in large populations. The objective of the present study was to determine comparatively biological responses of mesothelial Met-5A and monocyte-macrophage J774 cells following exposure to two types of fluoro-edenite fibers having low and high iron content (labeled 19 and 27, respectively) obtained from Biancavilla (Sicily, Italy). The reference fiber was a non-iron fibrous tremolite from Val di Susa (Piemonte, Italy). The cells were treated with 5, 50, and 100 mug of fibrous matter per 1 ml for 72 hr. We identified several key mechanisms by which cells responded and counteracted the injury induced by these fibers. The fibers caused induction of the heat shock protein 70 (Hsp70), stimulated formation of reactive oxygen species (detected by using DCFH-DA as a fluorescent probe) and NO* (measured as nitrite). Exposure of cells to the fibers induced lactate dehydrogenase activity and decreased viability. The fluoro-endenite type 27 was the most potent fiber tested, which indicated that iron and possibly manganese contribute significantly to this fiber toxicity. The J774 cells were more sensitive to fluoro-edenite than Met-5A cells suggesting that the primary site of the fiber-induced inflammatory response could be the macrophage rather than the pulmonary epithelium. Fluoro-edenite produces more biological alterations with respect to non-iron tremolite. Hsp70 and free radicals could be important factors in the context of mineral fiber-induced acute lung injury leading possibly to mutagenic effects. We anticipate that pharmacological blockade of the fiber-dependent cellular responses could in long term offer preventive approach to combat lung diseases induced by these fibers.
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PMID:Fluoro-edenite fibers induce expression of Hsp70 and inflammatory response. 1791 57

Lung cancer is characterized by abnormal cell growth and invasion, and the actin cytoskeleton plays a major role in these processes. The focal adhesion protein paxillin is a target of a number of oncogenes involved in key signal transduction and important in cell motility and migration. In lung cancer tissues, we have found that paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor (EGFR) gene copy numbers, or mutated (somatic mutation rate of 9.4%, 18 of 191). Paxillin mutations (19 of 21) were clustered between LD motifs 1 and 2 and the LIM domains. The most frequent point mutation (A127T) enhanced lung cancer cell growth, colony formation, focal adhesion formation, and colocalized with Bcl-2 in vitro. Gene silencing from RNA interference of mutant paxillin led to reduction of cell viability. A murine in vivo xenograft model of A127T paxillin showed an increase in tumor growth, cell proliferation, and invasion. These results establish an important role for paxillin in lung cancer.
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PMID:Paxillin is a target for somatic mutations in lung cancer: implications for cell growth and invasion. 1817 5

EGFR is a tyrosine kinase (TK) receptor overexpressed in lung adenocarcinomas. EGF binding to EGFR leads to K-Ras activation, promoting signaling of division, survival, and cell invasion. Adenocarcinomas addicted to EGFR signaling pathway for proliferation (10%), exhibit mutations of EGFR tyrosine kinase domain. Inhibition of these mutated receptors favors apoptosis signaling, taking account for dramatic tumoral responses. On the other side, 30% of adenocarcinomas have K-Ras mutations making the cells resistant to EGFR TK inhibitors (TKI). Secondary resistances are induced in 50% of initially sensitive tumors by an additional EGFR mutation (T790M), lowering receptor affinity for the inhibitor. The use of high affinity inhibitors ("irreversible") is tested in those patients. In 30% of cases, secondary resistance to TKI is induced by amplification of C-Met gene that encodes for another TK receptor, stimulating cell survival by substitution to EGFR. The use of C-Met inhibitors could overcome this kind of resistance. Angiogenesis is an early event in lung cell cancerization of which main cell signaling uses TK receptors to VEGF. Inhibition of this pathway consists in a major therapeutic advance in solid tumors. Finally, stimulation of anti-tumoral immunological response using anti-tumoral "vaccination", or agonists of innate immunity receptors, has given encouraging therapeutic preliminary results in lung cancer but needs phase 3 validation trials.
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PMID:[Mechanisms of action of targeted therapies... and mechanisms of resistance]. 1823 12

Although non-small cell lung cancer (NSCLC) cells with somatic mutations in their epidermal growth factor receptors (EGFR) initially show a dramatic response to tyrosine kinase inhibitor (TKI), these cells eventually develop resistance to TKI. This resistance may be caused by a secondary T790M mutation in the EGFR tyrosine kinase, which leads to the substitution of methionine for threonine in 790. In this study, we show that a combination of lapatinib and cetuximab overcomes gefitinib resistance in NSCLC with the T790M mutation. We observed that T790M lung cancer cells were resistant to gefitinib, and Stat3 was persistently activated in the resistant cells. A reversible EGFR and HER2 TKI, lapatinib, decreased Stat3 activation by blocking heterodimerization of EGFR and HER2, which led to a modest increase in the inhibitory effect on gefitinib-resistant T790M cells. In addition to lapatinib, the anti-EGFR antibody, cetuximab, induced down-regulation of EGFR and apoptotic cell death in T790M cells. Finally, combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC.
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PMID:Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells. 1834 47

For patients with advanced non-small cell lung cancer (NSCLC), the introduction of the epi- dermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, into clinical practice was promising. Treatment with either of these agents is associated with an objective response in 10-20% of patients. Subsequent studies have shown that patients responsive to gefitinib/erlotinib have tumours containing somatic activating mutations in the EGFR gene. Although impressive clinical and radiological responses have been observed in these patients, tumour progression occurs after the prolonged administration of gefitinib/erlotinib as acquired resistance develops. In order to combat acquired resistance, research has been largely focused on determining the factors underlying it. Two resistance mechanisms have so far been identified: a secondary mutation in the EGFR gene, T790M, and amplification of the MET proto-oncogene. This review will centre on T790M, which is thought to cause steric hindrance and impair the binding of gefitinib/erlotinib. A novel class of irreversible TKIs currently under development may retain activity against some common resistance mechanisms, including T790M. The next challenge is to identify accurately the subgroup of patients with NSCLC whose tumours harbour EGFR T790M. To this end, post-treatment tumour specimens will be needed to establish molecular profiles for each patient. In addition, novel, highly sensitive technology will be required to detect these mutations. This is because allelic dilution, whereby the EGFR gene is amplified but only a few copies of the T790M allele are needed to confer resistance, may obscure results of conventional sequencing methods. The importance of identifying patients who harbour T790M cannot be overstated; the development of irreversible TKIs will have profound implications for their treatment. In this way, treatment strategies in NSCLC are becoming increasingly tailored to the individual, and may set an example for other areas of oncology.
Lung Cancer 2008 Jun
PMID:Challenges of detecting EGFR T790M in gefitinib/erlotinib-resistant tumours. 1851 82

The heat shock protein 90 (Hsp90) chaperone is required for the conformational maturation and stability of multiple oncogenic kinases that drive signal transduction and proliferation of lung cancer cells. The recent demonstration that mutant epidermal growth factor receptor is an Hsp90 client, irrespective of the presence of the secondary threonine-to-methionine amino acid substitution mutation at position 790 mediating anilinoquinazoline resistance, suggests Hsp90 inhibition as a novel strategy against this group of lung cancers. The rarer epidermal growth factor receptors harboring exon 20 insertions and vIII mutations are also Hsp90 clients. Lung cancers may also be driven by mutant ErbB2, mutant B-Raf, or mutant or overexpressed c-Met, all of which are also degraded on Hsp90 inhibition. Hsp90 inhibitors may be synergistic with other drugs that disrupt chaperone function, including inhibitors of histone deacetylase 6 and the proteasome and agents that inhibit Hsp70 function. Hsp90 plays a unique antiapoptotic role in small cell lung cancer cells, so that Hsp90 inhibition results in substantial cell death in both chemosensitive and chemoresistant small cell lung cancer cell lines. Clinically, the geldanamycin compounds are the most mature, with manageable toxic effects. Several new classes of Hsp90 inhibitors are emerging, including purines and pyrazoles that have entered phase 1 trials. The available data suggest that Hsp90 inhibitors should be evaluated in multiple lung cancer subsets.
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PMID:Heat shock protein 90 inhibition in lung cancer. 1852 Mar 2

The receptor tyrosine kinase MET has been studied of a large variety of human cancers, including lung and mesothelioma. The MET receptor and its ligand HGF (hepatocyte growth factor) play important roles in cell growth, survival and migration, and dysregulation of the HGF-MET pathway leads to oncogenic changes including tumor proliferation, angiogenesis and metastasis. In small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and malignant pleural mesothelioma (MPM), MET is dysregulated via overexpression, constitutive activation, gene amplification, ligand-dependent activation, mutation or epigenetic mechanisms. New drugs targeted against MET and HGF are currently being investigated in vitro and in vivo, with promising results. These drugs function at a variety of steps within the HGF-MET pathway, including MET expression at the RNA or protein level, the ligand-receptor interaction, and tyrosine kinase function. This paper will review the structure, function, mechanisms of tumorigenesis, and potential for therapeutic inhibition of the MET receptor in lung cancer and mesothelioma.
Lung Cancer 2009 Feb
PMID:MET as a target for treatment of chest tumors. 1867 14


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