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

The epidermal growth factor receptor (EGFR) is overexpressed and activated in many human cancers and predicts poor patient prognosis. Targeting the kinase domain with specific EGFR tyrosine kinase inhibitors (TKIs) like gefitinib and erlotinib has been used in anticancer treatments. However, patient response rates in different human cancers were initially low. Only a subgroup of non-small-cell lung cancer (NSCLC) patients harboring EGFR-activating mutations responds to EGFR TKI treatment, but most of these responders relapse and acquire resistance. Recent clinical studies have demonstrated that MET proto-oncogene overexpression correlates with resistance to EGFR TKI treatment. Similarly to MET overexpression, the tumor microenvironment-derived ligand hepatocyte growth factor (HGF) was shown to activate Met and thereby induce short-term resistance to EGFR TKI treatment in gefitinib-sensitive NSCLC cell lines in vitro. However, only little is known about the HGF/Met-induced EGFR TKI resistance mechanism in other human cancer types. Therefore, in order to develop possible new anticancer strategies for diverse human cancers, we screened 12 carcinoma cell lines originating from the breast, kidney, liver and tongue for HGF-induced EGFR tyrosine kinase (TK)-inhibition. In addition, in order to advance our understanding of a TK-inactive EGFR, we used EGFR co-immunoprecipitation, followed by mass spectrometry to identify novel HGF-induced EGFR binding partners, which are potentially involved in tyrosine kinase-independent EGFR signaling mechanisms. Here we show for the first time that HGF-induced EGFR TK-inhibition is a very common mechanism in human cancers, and that the kinase-inactive EGFR directly interacts with and stabilizes several cancer-relevant proteins, including the receptor tyrosine kinases Axl and EphA2, and the CUB domain-containing protein-1. This study has strong implications for the development of new anticancer strategies.
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PMID:HGF induces novel EGFR functions involved in resistance formation to tyrosine kinase inhibitors. 2304 85

MET is a tyrosine kinase receptor for hepatocyte growth factor (HGF), primarily expressed on epithelial cells; the activation of MET induces several biological responses relevant for the development and growth of many human cancers. Several human malignancies present altered expression of MET and this is usually associated with poor prognosis and aggressive phenotype. The majority of MET inhibitors in clinical development target directly the receptor through the use of monoclonal antibodies (MAbs) or through small molecule inhibitors of MET kinase activity; small molecule inhibitors are very potent but less specific than MAbs. MET inhibitors are of great clinical interest because of the extensive crosstalk of the HGF/MET axis with many other signaling pathways, including growth factor-dependent pathways (like PI3K/AKT/mTOR,RAS/RAF/ERK) and vascular endothelial growth factor (VEGF) axis. In preclinical studies, the treatment with MET inhibitors could prevent or reverse resistance to inhibitors of growth factor-dependent signaling; this hypothesis is currently tested in phase III trials with anti-epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). Based on preclinical and preliminary clinical results, a rational strategy for the clinical development of MET antagonists should include a selection of the tumors with MET overexpression, the identification of prognostic/predictive biomarkers, the evaluation of combinations with anti-VEGF compounds.
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PMID:Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist. 2311 Aug 8

The only approved agents for second-line therapy in unselected non-small-cell lung cancer are docetaxel and pemetrexed (chemotherapies) and erlotinib (targeted therapies). Several new molecular drugs have now entered clinical trials and are being compared with approved agents (e.g., vandetanib). Alternative pathways are also being explored to overcome resistance to established agents (c-MET and ALK inhibitors), and predictive factors are now crucial for the selection of drug and of patients (e.g., EGFR mutations). Better patient selection permits second-line treatment to be tailored according to disease identity, which confers a particular benefit in certain subgroups of patients. In this review, the authors examine existing trials comparing targeted therapies with the standard of care as second-line therapy for advanced non-small-cell lung cancer.
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PMID:Biological agents alone or in combination as second-line therapy in advanced non-small-cell lung cancer: systematic review of randomized studies. 2317 18

There are several challenges in lung cytology including equivocal cytological findings, lung cancer subclassification, and predictive marker analysis. Fluorescence in situ hybridization (FISH) detects chromosomal alterations that underlie the development and progression of cancer, and pinpoints targets of new anticancer drugs. Detection of such targets by FISH can be of diagnostic utility in morphologically difficult cases. Multitarget FISH with four different chromosomal probes improves the sensitivity of cytology in the diagnosis of lung cancer and clarifies equivocal cytological findings. FISH is becoming increasingly important in the field of predictive marker analysis. FISH is the gold standard to identify ALK rearrangements for treatment with the ALK inhibitor crizotinib (Xalkori). EGFR mutation analysis is the method of choice for selecting patients for therapy with EGFR tyrosine kinase inhibitors (TKIs), whereas the EGFR gene copy number has not been confirmed as a reliable predictive marker. MET amplification is an important mechanism of secondary resistance to EGFR TKIs and a candidate predictive marker for targeted second-line treatment of TKI-resistant non-squamous non-small cell lung cancer. FGFR1 amplification is a promising new marker in squamous cell carcinoma that may predict the response to FGFR1 inhibitors. In conclusion, there are an increasing number of clinically relevant FISH applications in lung cytology. We provide an overview on the current role of FISH in respiratory cytology.
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PMID:Role of fluorescence in situ hybridization in lung cancer cytology. 2320 39

Cancer is now known as a disease of genomic alterations. Mutational analysis and genomics profiling in recent years have advanced the field of lung cancer genetics/genomics significantly. It is becoming more accepted now that the identification of genomic alterations in lung cancer can impact therapeutics, especially when the alterations represent "oncogenic drivers" in the processes of tumorigenesis and progression. In this review, we will highlight the key driver oncogenic gene mutations and fusions identified in lung cancer. The review will summarize and report the available demographic and clinicopathological data as well as molecular details behind various lung cancer gene alterations in the context of race. We hope to shed some light into the disparities in the incidence of various genetic mutations among lung cancer patients of different racial backgrounds. As molecularly targeted therapy continues to advance in lung cancer, racial differences in specific genetic/genomic alterations can have an important impact in the choices of therapeutics and in our understanding of the drug sensitivity/resistance profile. The most relevant genes in lung cancer described in this review include the following: EGFR, KRAS, MET, LKB1, BRAF, PIK3CA, ALK, RET, and ROS1. Commonly identified genetic/genomic alterations such as missense or nonsense mutations, small insertions or deletions, alternative splicing, and chromosomal fusion rearrangements were discussed. Relevance in current targeted therapeutic drugs was mentioned when appropriate. We also highlighted various targeted therapeutics that are currently under clinical development, such as the MET inhibitors and antibodies. With the advent of next-generation sequencing, the landscape of genomic alterations in lung cancer is expected to be much transformed and detailed in upcoming years. These genomic landscape differences in the context of racial disparities should be emphasized both in tumorigenesis and in drug sensitivity/resistance. It is hoped that such effort will help to diminish racial disparities in lung cancer outcome in the future.
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PMID:Cancer genes in lung cancer: racial disparities: are there any? 2326 47

The anaplastic lymphoma kinase (ALK) fusion gene is a key oncogenic driver in a subset of patients with advanced non-small cell lung cancer (NSCLC). Oncogenic fusion genes, including echinoderm microtubule-associated protein-like 4 (EML4) and ALK, have been detected in approximately 2-7 % of NSCLC patients. Fluorescence in situ hybridization (FISH) is the recommended method for detecting ALK gene rearrangement. EML4-ALK fusion genes define a molecular subset of NSCLC with distinct clinical characteristic (lung adenocarcinoma, never or former smoker, usually mutually exclusive with EGFR mutations). Crizotinib (PF-02341066) is an orally bioavailable, ATP-competitive, small molecule inhibitor of both the receptor tyrosine kinases ALK and c-MET (hepatocyte growth factor receptor). Crizotinib has been shown to yield important clinical benefit such as objective response rate, progression-free survival (PFS), and anticipated improvements in quality of life when used in pretreated patients with advanced NSCLC harboring EML4-ALK gene rearrangement. Preliminary phase II data suggested that crizotinib is safe and well tolerated with rapid and robust antitumor activity. A phase III randomized trial in a second-line setting showed response rate and PFS (primary study endpoint) advantage for crizotinib as compared to second-line chemotherapy. Treatment-related adverse events, predominantly restricted to the gastrointestinal and visual systems, are generally self-limiting or easily managed. Crizotinib is a new standard of care for patients with advanced, ALK-positive, NSCLC. In this review, we will discuss the discovery of ALK rearrangements, the clinical epidemiology of lung cancer driven by ALK, the clinical data for ALK-targeted therapy in NSCLC, and ongoing ALK inhibitor-based clinical trials.
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PMID:ALK inhibitors: a new targeted therapy in the treatment of advanced NSCLC. 2332 96

Growth factor receptors (GFRs) are amenable to therapeutic intervention in cancer and it is important to select patients appropriately. One of the mechanisms for activation of GFRs is gene amplification (GA) but discrepancies arising from the difficulties associated with data interpretation and the lack of agreed parameters confound the comparison of results from different laboratories. Here, we attempt to establish appropriate conditions for standardization of the determination of GA in a panel of GFRs. A NSCLC tissue microarray panel containing 302 samples was screened for alterations at ALK, FGFR1, FGFR2, FGFR3, ERBB2, IGF1R, KIT, MET and PDGFRA by FISH, immunostaining and/or real-time quantitative RT-PCR. Strong amplification was found for FGFR1, ERBB2, KIT/PDFGRA and MET, with frequencies ranging from 1 to 6%. Thresholds for overexpression and GA were established. Strong immunostaining was found in most tumors with ERBB2, MET and KIT amplification, although some tumors underwent strong immunostaining in the absence of GA. KIT and PDFGRA were always coamplified, but only one tumor showed PDGFRA overexpression, indicating that KIT is the main target. Amplification of FGFR1 predominated in squamous cell carcinomas, although the association with overexpression was inconclusive. Interestingly, alterations at ALK, MET, EGFR, ERBB2 and KRAS correlated with augmented levels of phospho-S6 protein, suggesting activation of the mTOR pathway, which may prove useful to pre-select tumors for testing. Overall, here, we provide with parameters for the determination of GA at ERBB2, MET, KIT and PDGFRA which could be implemented in the clinic to stratify lung cancer patients for specific treatments.
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PMID:Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer. 2340 Jun 71

Lung cancer is a heterogeneous group of disorders that is now being subdivided into molecular subtypes with dedicated targeted therapies. The MET receptor tyrosine kinase has been identified as aberrantly overexpressed, potentially having activating mutations, and amplified in certain subsets of lung cancers. The ligand hepatocyte growth factor (HGF) can also be overexpressed in lung cancer or expressed in stroma, and both the MET receptor and the HGF ligand can be targets for therapeutics, especially in lung cancer. Activation of MET leads to a plethora of biochemical and biologic changes both in normal and cancerous cells. Preclinically, it has been shown that silencing or inactivating MET leads to decreased viability of cancer cells. There are a number of compounds against MET/HGF in clinical trials that have been shown to be active in lung cancers. This review will summarize the biology of MET as well as its therapeutic inhibition in lung cancer.
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PMID:MET as a possible target for non-small-cell lung cancer. 2340 58

Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC). However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22-q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer.
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PMID:Mouse model for ROS1-rearranged lung cancer. 2341 94

Lung cancer treatment has rapidly changed in the last few years thanks to novel insights into cancer biology. Several biomarkers and signaling pathways have been recognized as conceivable targets for treatment, and among them is the mesenchymal-epithelial transition/hepatocyte growth factor (c-MET/HGF) axis. Alterations in the c-MET gene and aberrations of MET and HGF expression impact on lung cancer prognosis and are involved in resistance to epidermal growth factor receptor (EGFR) inhibitors in non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. Several anti-MET and anti-HGF strategies are currently under investigation, including monoclonal antibodies. Ficlatuzumab is a monoclonal antibody directed against HGF that is currently under investigation in NSCLC. The aim of the present review is to critically review available data on HGF and ficlatuzumab in NSCLC.
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PMID:Focus on the potential role of ficlatuzumab in the treatment of non-small cell lung cancer. 2349 85


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