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 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.
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PMID:Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. 1767 92

A subset of lung cancers harbors a small inversion within chromosome 2p, giving rise to a transforming fusion gene, EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene), which encodes an activated tyrosine kinase. We have earlier examined the presence of EML4-ALK by multiplex reverse transcription-polymerase chain reaction in 363 specimens of lung cancer, identifying 11 adenocarcinoma cases featuring the fusion gene. In this study, we clinicopathologically examined the characteristics of the EML4-ALK-positive cases, including the mutation status of EGFR, KRAS, and TP53, and whether they were of thyroid transcription factor-1 (TTF-1) cell lineage or not. Of 11 patients, 4 (36%) with EML4-ALK-positive lung adenocarcinomas who were below 50 years of age were affected by these diseases, as compared with 12 of 242 patients (5.0%) with EML4-ALK-negative lung adenocarcinomas (P=0.00038). EML4-ALK-positive lung adenocarcinomas were characterized by less-differentiated grade (P=0.0082) and acinar-predominant structure (P<0.0001) in histology. Furthermore, the presence of EML4-ALK appears to be mutually exclusive for EGFR and KRAS mutations (P=0.00018), whereas coexisting with TP53 mutations at a low frequency (1/11=9.1%), and correlating with non- or light smoking (P=0.040), in line with the TTF-1 immunoreactivity. Thus, EML4-ALK-positive tumors may form a distinct entity among lung adenocarcinomas, characterized by young onset, acinar histology, no or rare mutations in EGFR, KRAS, and TP53, and a TTF-1 cell lineage, all in agreement with the prevalence in non- or light smokers.
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PMID:EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. 1923 40

The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as an oncogene in a subset of non-small cell lung cancers (NSCLC). We used profiling of cancer genomes on an exon array to develop a novel computational method for the global search of gene rearrangements. This approach led to the detection of EML4-ALK fusion in breast and colorectal carcinomas in addition to NSCLC. Screening of a large collection of patient tumor samples showed the presence of EML4-ALK fusion in 2.4% of breast (5 of 209), 2.4% of colorectal (2 of 83), and in 11.3% of NSCLC (12 of 106). Besides previously known EML4-ALK variants 1 (E13; A20) and 2 (E20; A20), a novel variant E21; A20 was found in colorectal carcinoma. The presence of an EML-ALK rearrangement was verified by identifying genomic fusion points in tumor samples representative of breast, colon, and NSCLC. EML4-ALK translocation was also confirmed by fluorescence in situ hybridization assay, which revealed its substantial heterogeneity in both primary tumors and tumor-derived cell lines. To elucidate the functional significance of EML4-ALK, we examined the growth of cell lines harboring the fusion following EML4 and ALK silencing by small interfering RNA. Significant growth inhibition was observed in some but not all cell lines, suggesting their variable dependence on ALK-mediated cell survival signaling. Collectively, these findings show the recurrence of EML4-ALK fusion in multiple solid tumors and further substantiate its role in tumorigenesis.
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PMID:Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. 1973 69

Transforming rearrangements of the ALK (anaplastic lymphoma kinase) gene have recently been described in non-small cell lung cancer (NSCLC). The most common rearrangement arises from an inversion in the short arm of chromosome 2 that creates a fusion between the 5' portion of the EML4 (echinoderm microtubule-associated protein-like 4) gene and the 3' portion of the ALK gene. At least seven ALK gene rearrangement variants have been described involving different EML4-ALK breakpoints or rarely other non-EML4 fusion partners. ALK rearrangements may be readily identified in tumor tissue by reverse transcription-polymerase chain reaction or fluorescent in situ hybridization. Although ALK gene rearrangements affect only about 4% of all lung cancers, they are more frequent in adenocarcinomas, in never or light smokers, and seem almost mutually exclusive with activating EGFR or KRAS mutations. Promising results seen in patients with NSCLC containing fluorescent in situ hybridization-detected ALK rearrangements treated on a phase I study with PF02341066, an oral ALK inhibitor, indicate that ALK represents a new therapeutic target in this molecularly defined subset of NSCLC.
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PMID:ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. 2233 10

Recent progress in molecular biology has shown that cancer cells acquire common phenotypes such as self-sufficiency of growth signals, resistance to anti-proliferative and apoptotic signals through the accumulation of genetic and epigenetic changes. Recently developed anticancer drugs target these molecular mechanisms and good results have been reported for various cancer types. In lung cancer, tyrosine kinase inhibitors specific for the epidermal growth factor receptor such as gefitinib and erlotinib have changed clinical practice dramatically. About half of the Japanese patients with lung cancers harbor an activating mutation of the epidermal growth factor receptor gene and they are very sensitive to epidermal growth factor receptor tyrosine kinase inhibitors. Progression-free survival of such patients is approximately 10 months when treated with gefitinib, whereas the survival for those treated with platinum doublet therapy is approximately 6 months. Target therapies against echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion protein or a mutated ERBB2 (v-ERB-B avian erythroblastic leukemia viral oncogene homologue 2) present in approximately 5% and approximately 3% of the Japanese patients with adenocarcinomas, respectively, are currently under development. Addition of an anti-epidermal growth factor receptor antibody, cetuximab, or anti-vascular endothelial growth factor antibody, bevacizumab, to platinum doublet therapy significantly but modestly prolonged the survival in recent clinical trials. However, clinical development of small molecule multi-kinase inhibitors including those targeting vascular endothelial growth factor receptors, such as vandetanib, sunitinib and sorafenib, has not been very successful. Through these collaborations among clinicians, basic researchers and pharmaceutical companies, it should be possible to individualize lung cancer treatment to turn this fatal disease into a chronic disorder and, eventually, to cure it.
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PMID:Advances in target therapy for lung cancer. 2003 62

Genetic alterations of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) inversion were recently found in lung cancer. A 39-year-old woman with multiple brain metastases and bulky mediastinal lymph node metastases was admitted. Biopsy from her supraclavicular lymph nodes was performed to differentiate the diagnosis between lymphoma and lung cancer. Pathologically, the lymph nodes had a feature of adenocarcinoma. On the other hand, the commercially available chromosomal fluorescent in situ hybridization (FISH) analysis showed split signals of ALK, which was confirmed to be the EML4-ALK inversion. The commercial-based ALK FISH is useful for screening pulmonary ALKoma.
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PMID:Incidentally proven pulmonary "ALKoma". 2022

The fusion between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) has recently been identified in a subset of non-small cell lung cancers (NSCLCs). EML4-ALK is most often detected in never smokers with lung cancer and has unique pathologic features. EML4-ALK is oncogenic both in vitro and in vivo and ALK kinase inhibitors are quite effective in pre-clinical model systems. More recently ALK inhibitors have entered clinical development and remarkably clinical efficacy has been observed in NSCLC patients harbouring EML4-ALK translocations. This review will focus on the biology, clinical characteristics, diagnosis and treatment of EML4-ALK NSCLC.
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PMID:The biology and treatment of EML4-ALK non-small cell lung cancer. 2041 96

The fusion gene EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) was recently identified as a novel genetic alteration in non-small-cell lung cancer. The clinicopathological features of EML4-ALK-positive adenocarcinoma are reported to include its high incidence in young, non-smoking patients, tumors that show distinct solid or acinar growth patterns with or without signet-ring cell histology, and its mutually exclusive occurrence with mutations in EGFR and KRAS. However, the clinical findings have not been well described. Here, we report a case of EML4-ALK-positive lung adenocarcinoma that showed multiple metachronous lesions on the pleura and pulmonary field, suspected to be a recurrence of lung adenocarcinoma after a 20-year disease-free interval. The slow clinical course may be characteristic of EML4-ALK-positive lung adenocarcinoma. Therefore, long-term observation of patients with EML4-ALK-positive lung adenocarcinomas is required after surgery.
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PMID:Recurrent EML4-ALK-associated lung adenocarcinoma with a slow clinical course. 2065 20

The EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers, and clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way. Here, we report the discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to two different ALK inhibitors. (Funded by the Ministry of Health, Labor, and Welfare of Japan, and others.).
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PMID:EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. 2134 11

The fusion gene EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) was recently identified as a novel genetic alteration in non-small cell lung cancer (NSCLC). EML4-ALK translocations correlate with specific clinical and pathological features, in particular lack of EGFR and K-ras mutations, and may be associated with resistance to EGFR tyrosine-kinase inhibitors (TKIs). Here, we report a case of a patient with a concomitant EGFR mutation and ALK translocation resistant to erlotinib. Considering this report, ALK status should be investigated in unexplained cases of EGFR-TKI-resistance of EGFR mutated NSCLCs.
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PMID:EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. 2116 33


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