Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The year 2009 has lead to new data clearly impacting therapeutic management strategies in NSCLC. Personalized medicine is becoming a reality for patients with EGFR mutation as well as for the recruitment of patients in certain clinical trials (EML4-ALK translocation, KRAS mutation...). Maintenance trials are based on questionable statistical designs but this approach may have an interest in certain subset of patients. Little improvements are being achieved in SCLC and locally advanced NSCLC.
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PMID:[Lung cancer: an update in 2010]. 2002 51

The anaplastic lymphoma kinase gene (ALK) is a gene on chromosome 2p23 that has expression restricted to the brain, testis and small intestine but is not expressed in normal lymphoid tissue. It has similarity to the insulin receptor subfamily of kinases and is emerging as having increased pathologic and potential therapeutic importance in malignant disease. This gene was originally established as being implicated in the pathogenesis of rare diseases including inflammatory myofibroblastic tumour (IMT) and ALK-positive anaplastic large cell lymphoma, which is a subtype of non-Hodgkin's lymphoma. Recently the number of diseases in which ALK is implicated in their pathogenesis has increased. In 2007, an inversion of chromosome 2 involving ALK and a fusion partner gene in a subset of non-small cell lung cancer was discovered. In 2008, publications emerged implicating ALK in familial and sporadic cases of neuroblastoma, a childhood cancer of the sympatho-adrenal system. Chromosomal abnormalities involving ALK are translocations, amplifications or mutations. Chromosomal translocations are the longest recognised ALK genetic abnormality. When translocations occur a fusion gene is created between ALK and a gene partner. This has been described in ALK-positive anaplastic large cell lymphoma in which ALK is fused to NPM (nucleolar protein gene) and in non-small cell lung cancer where ALK is fused to EML4 (Echinoderm microtubule-associated protein 4). The most frequently described partner genes in inflammatory myofibroblastic tumour are tropomyosin 3/4 (TMP3/4), however in IMTs a diversity of ALK fusion partners have been found, with the ability to homodimerise a common characteristic. Point mutations and amplification of the ALK gene occur in the childhood cancer neuroblastoma. Therapeutic targeting of ALK fusion genes using tyrosine kinase inhibition, vaccination using an ALK specific antigen and treatment using viral vectors for RNAi are emerging potential therapeutic possibilities.
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PMID:The emerging pathogenic and therapeutic importance of the anaplastic lymphoma kinase gene. 2045 71

The anaplastic lymphoma kinase gene (ALK) code for a receptor tyrosine-kinase. The fusion proteins from the ALK gene have been identified in oncohaematology malignancies including ALK positive anaplastic lymphoma large cell and non small cells lung cancer with EML4-ALK fusion gene. Constitutive activation generated by modification of this protein leads activation of anti apoptotic and survey pathways that makes it a prime target for these 2 subtypes of disease. Strategies and therapeutic molecules targeting the fusion protein are under development and preliminary results are encouraging. Therefore the mapping of the tumors is essential to help provide treatment specific to each entity. The best example is the chronic myeloid leukemia and the discovery of the fusion gene bcr-abl and of imatinib.
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PMID:[Implications of ALK (anaplastic lymphoma kinase) in oncohematology]. 2048 5

Treatment outcomes in advanced or metastatic non-small-cell lung cancer (NSCLC) remain unsatisfactory, with low long-term survival rates. Palliative chemotherapy offers a median survival not exceeding 1 year. To date, various combinations of cytotoxic drugs have not improved treatment results beyond what has been observed with platinum doublets. By contrast, molecular targeted drugs may block important pathways that drive cancer progression and achieve long-term disease control. Conflicting results have demonstrated marginal benefit with EGFR inhibitors, anti-EGFR monoclonal antibodies and antiangiogenic strategies in unselected populations of patients with advanced NSCLC. However, patients with an EGFR mutation are likely to respond to agents that target this gene. Novel targeted therapies that interfere with insulin-like growth factor 1 receptor, or the EML4-ALK fusion protein have shown promising activity. Aberrations in other key signaling pathways and molecules, such as RAS/RAF/MEK, PI3K/AKT/mTOR, or MET kinase, have been identified as crucial targets, especially in resistant patients. Novel drugs aimed at these abnormalities are already in the clinic. This Review outlines the current state-of-the-art research for targeted therapy in NSCLC.
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PMID:Targeted therapy in non-small-cell lung cancer--is it becoming a reality? 2055 45

In the past few years, we have witnessed a revolution in the molecular understanding of non-small cell lung cancer. Major progress has also been made in the clinic, with the introduction of EGFR-targeted and anti-angiogenic therapies. These advances have led to the development of a multitude of commercially available prognostic and predictive biomarkers. In particular, EGFR mutation and EML4/ALK testing have reached clinical validation and are incorporated into current treatment paradigms. This overview will present the scientific background of the biology of the relevant biomarkers and the studies conducted for their clinical validation. The technical challenges and shortcomings of these assays are also discussed. Furthermore, ongoing biomarker-driven clinical studies and the appropriate clinical use of available tests will be reviewed to assist the clinician with the proper incorporation of molecular testing into the routine care of patients with non-small cell lung cancer.
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PMID:Molecular testing in lung cancer: the time is now. 2062 7

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 development of molecular markers is crucial for improving therapy in advanced non-small cell lung cancer (NSCLC). Here, we review perspectives of biomarker-driven personalized therapy in NSCLC, with particular reference to the detection of EML4-ALK gene rearrangements. Different molecular assays, validation, and clinical application to different types of tissue specimens are discussed.
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PMID:The tissue is the issue: personalized medicine for non-small cell lung cancer. 2092 2

Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non-small cell lung cancer patients and rarely coexist with KRASor EGFR mutations. To evaluate potential treatment strategies for lung cancers driven by an activated EML4-ALK chimeric oncogene, we generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises. In this model, the ALK kinase inhibitor TAE684 produced greater tumor regression and improved overall survival compared with carboplatin and paclitaxel, representing clinical standard of care. 18F-FDG-PET-CT scans revealed almost complete inhibition of tumor metabolic activity within 24 hours of TAE684 exposure. In contrast, combined inhibition of the PI3K/AKT and MEK/ERK1/2 pathways did not result in significant tumor regression. We identified EML4-ALK in complex with multiple cellular chaperones including HSP90. In support of a functional reliance, treatment with geldanamycin-based HSP90 inhibitors resulted in rapid degradation of EML4-ALK in vitro and substantial, albeit transient, tumor regression in vivo. Taken together, our findings define a murine model that offers a reliable platform for the preclinical comparison of combinatorial treatment approaches for lung cancer characterized by ALK rearrangement.
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PMID:Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. 2095 6


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