Academic literature on the topic 'EML4-ALK fusion protein'
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Journal articles on the topic "EML4-ALK fusion protein"
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Richards, Mark W., Laura O'Regan, Daniel Roth, Jessica M. Montgomery, Anne Straube, Andrew M. Fry, and Richard Bayliss. "Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain." Biochemical Journal 467, no. 3 (April 17, 2015): 529–36. http://dx.doi.org/10.1042/bj20150039.
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Proteins of the echinoderm microtubule (MT)-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase MT network. EML1–4 consist of Trp-Asp 40 (WD40) repeats and an N-terminal region containing a putative coiled-coil. Recurrent gene rearrangements in non-small cell lung cancer (NSCLC) fuse EML4 to anaplastic lymphoma kinase (ALK) causing expression of several oncogenic fusion variants. The fusions have constitutive ALK activity due to self-association through the EML4 coiled-coil. We have determined crystal structures of the coiled-coils from EML2 and EML4, which describe the structural basis of both EML self-association and oncogenic EML4–ALK activation. The structures reveal a trimeric oligomerization state directed by a conserved pattern of hydrophobic residues and salt bridges. We show that the trimerization domain (TD) of EML1 is necessary and sufficient for self-association. The TD is also essential for MT binding; however, this property requires an adjacent basic region. These observations prompted us to investigate MT association of EML4–ALK and EML1–ABL1 (Abelson 1) fusions in which variable portions of the EML component are present. Uniquely, EML4–ALK variant 3, which includes the TD and basic region of EML4 but none of the WD40 repeats, was localized to MTs, both when expressed recombinantly and when expressed in a patient-derived NSCLC cell line (H2228). This raises the question of whether the mislocalization of ALK activity to MTs might influence downstream signalling and malignant properties of cells. Furthermore, the structure of EML4 TD may enable the development of protein–protein interaction inhibitors targeting the trimerization interface, providing a possible avenue towards therapeutic intervention in EML4–ALK NSCLC.
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Mao, Weimin, Mark Han, Zhiqiang Ling, Wenyong Sun, Gu Zhang, Hongshan Dong, and Yingzi Zhang. "Triple probe FISH approach for detecting EML4-ALK gene rearrangement in Chinese patients with NSCLC." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e21080-e21080. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e21080.
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e21080 Background: The echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion represents a novel target for the therapy of a subset of non-small cell lung cancer (NSCLC). ALK rearrangement has been found in approximately 1.6–11.6% of NSCLC in unselected patient populations, but the frequency also varied when different diagnostic approach was used. We, for the first time, investigated frequency of EML4-ALK rearrangement in unselected Chinese patients with NSCLC using recent developed fluorescence in situ hybridization (FISH) triple color break-apart probe. Methods: One hundred-thirty one FFPE specimens from NSCLC patients were collected for the investigation. Fusion between 3’ portion of ALK gene and the 5’ portion of EML4 gene was detected using FISH tri-check probe (ZytoVision, Germany). Positive cells were defined as having any signal A ( distance more than two-time the ALK signal size) or signal B ( distance between one- and two-time the ALK signal size plus EML4 translocation signal) or any isolated ALK 3’ signal. Total 100 nuclei for each specimen were counted. Specimen was as classified as EML4-ALK rearrangement when the proportion of positive cells was over 15%. ALK/EML4 signals over 6 in over 10% nuclei were classified as gene amplification. Results: Of 131 specimens, frequency of ALK rearrangement was 10.7% (14/131) when positive cells were counted by signal A and isolated ALK 3’ signal (dual color). Frequency of EML4-ALK rearrangement was 13.0% (17/131) when positive cells were counted by signal A, B and isolated ALK 3’ signal (triple color), in which 21% (17/14) more cases were classified as EML4-ALK rearrangement comparing dual color enumeration. ALK and EML4 amplification were observed in 2.3% (3/131) specimens, respectively, in which two were co-amplified and none of them had EML4-ALK rearrangement. Conclusions: Present result showed that frequency of EML4-ALK rearrangement in unselected Chinese patients with NSCLC was 13.0% determined by FISH tri-check probe. This study suggested that counting both ALK inversion and EML4 translocation may contribute to defining EML4-ALK positive cells.
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Papadopoulou, Eirini, Samuel Murray, and George Nasioulas. "Development of a novel RT-PCR assay for the detection of EML4-ALK fusion products in FFPE speciments." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e21087-e21087. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e21087.
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e21087 Background: EML4-ALK is a fusion-type protein tyrosine kinase identified recently in a subset of human lung carcinomas and seems to be a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC. To date, several EML4-ALK variants have been identified in lung cancer samples. Three methods have been used for the detection of these fusions, including IHC, FISH, and RT-PCR, which is the only method that can distinguish between different variants. Existing RT-PCR methods, are designed to amplify large cDNA fragments and are inadequate for the analysis of formalin-fixed paraffin-embedded (FFPE) tissues which produce cDNA fragments of limited size. Thus, we designed an RT-PCR assay that can detect all published EML4-ALK variants and is suitable for use with this commonly available material. Methods: Synthetic DNA fragments for each variant were cloned using the pCR2.1 cloning vector and used as positive controls. Specific primers that enhance specifically EML4-ALK transcripts 1, 2, 3a, 3b, 4, 5a, 5b, 6, 7, "4", and "5" were designed. Detection of all EML4-ALK fusions was achieved using RT-PCR. DNA sequencing analysis was performed to confirm the specificity of the obtained PCR products. The sensitivity of the method was calculated by adding to 1μg RNA serial dilutions of the synthetic DNA fragments. It was found that up to 22 copies of the translocation can be detected per μg of RNA. The study included FFPE specimens from NSCLC patients without EGFR and K-RAS mutations. Pathological review was obtained for all samples and macro-dissection was used to ensure a tumor cell content of >75%. We are currently increasing our sample size of Greek patients and are in collaboration with other centers to further understand the clinical impact of the variant spectrum. Results: Three control EML4-ALK FISH positive samples were positively subtyped using RT-PCR and sequencing. None of the 96 FFPE specimens tested so far was positive for the EML4-ALK fusion. Conclusions: We designed a robust multiplex RT-PCR assay that permits the sensitive detection of all published EML4-ALK variants. It’s suitable for use with commonly available materials such as FFPE specimens, cytological specimens and other aspirates.
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Su, Kang-Yi, Bing-Ching Ho, Gee-Chen Chang, Hsuan-Yu Chen, Pan-Chyr Yang, and Sung-Liang Yu. "Multiplex ALK, RET, and ROS1 fusion mutation detection in FFPE from lung cancer patients by MALDI-TOF mass spectrometry." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e13103-e13103. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e13103.
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e13103 Background: Approximately 3-7% of lung tumors harbor anaplastic lymphoma kinase (ALK) fusions in the subgroup of non-small cell lung cancer (NSCLC). In addition to echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion, TRK-fused gene (TFG)-ALK, kinesin family member 5B (KIF5B)-ALK and kinesin light chain 1 (KLC1)-ALK had been reported in lung cancer. On the other hand, RET proto-oncogene (RET) and ROS proto-oncogene 1 (ROS1) fusion proteins also have prevalence in lung cancer. Food and Drug Administration (FDA)-approved several target drugs are available to treat patients with fusion mutations. Therefore, the diagnosis of ALK, RET or ROS1 fusion genes shows quite important. However, nowadays methods of detecting fusions such as fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are limited to technique, low sensitivity, sample quality as well as subtype classification. Methods: We established nucleotide MALDI-TOF mass spectrometry based multiplex detection platform to distinguish major types including 9 types of EML4-ALK, 5 types of ALK, 5 types of RET and 8 types ROS1 fusions. Results: The detection limitation was about less 1% mutant cells among wild-type cells. In the pilot testing, we used 2 patients’ cell cDNA and 4 patients’ lung FFPE samples cDNA, which had been diagnosed as ALK fusion before, to be detected by this panel, and then identified their variant types successfully. Furthermore, one patient harbored CCDC6-RET fusion mutation was identified by our platform and confirmed by Sanger Sequencing. Conclusions: Taken together, this new panel has high sensitivity and allows little and poor quality samples for detecting. The correlation between clinical characteristics and fusion subtypes can be further investigated by utilizing this platform in the future. Also, the detection panel can be revised based on clinical needs by removing/adding probes.
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Gonzalez-Martinez, David, Lee Roth, Thomas Mumford, Yael Mosse, Asmin Tulpule, Trever Bivona, and Lukasz Jan Bugaj. "Abstract 848: Inhibition of RTK fusion condensates enhances signal perception and promotes drug tolerance." Cancer Research 82, no. 12_Supplement (June 15, 2022): 848. http://dx.doi.org/10.1158/1538-7445.am2022-848.
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Abstract Drug resistance remains a significant obstacle in the successful treatment of cancer, highlighting the critical need to understand how oncogenes and cancer drugs impact cell physiology and resistance development. EML4-ALK is a receptor tyrosine kinase (RTK) fusion oncogene that drives 3-7% of lung cancer. Despite potent ALK inhibitors, EML4-ALK+ cancers frequently develop resistance during therapy. Recently, it was discovered that EML4-ALK and other RTK fusions form cytoplasmic protein condensates, and that condensate formation was required for oncogenic signaling. However, whether oncogenic condensates play a role in drug responses is unclear. In this study, we applied an optogenetic technique called ‘functional profiling’ to understand how EML4-ALK condensates impact cell signal transmission and drug response. Using light-stimulated RTKs, we found that EML4-ALK condensates strongly suppress signaling through transmembrane RTKs, including through EGFR, a central receptor in resistance development. Strikingly, treatment with ALK inhibitors (ALKi) rapidly restored and hypersensitized RTK signaling. We found that EML4-ALK condensates suppress RTK signals through sequestration of the downstream adapter Grb2, which is essential for signaling through EGFR and other RTKs. The release of Grb2 from condensates resensitized RTKs within 10s of minutes of ALKi addition. Resensitized RTKs, in turn, caused sporadic RTK activation pulses throughout the cell population, and pulses originated from paracrine RTK signals released by apoptotic neighbors. We found that these paracrine signals counteracted ALK inhibitor therapy and promoted survival and drug tolerance. Blocking paracrine signals through co-treatment of ALKi with inhibitors of either EGFR or matrix metalloproteases enhanced cell killing and minimized long-term drug tolerance. Our study uncovers a role for oncogenic condensates in drug resistance signaling, reveals a novel mechanism for oncogene-induced suppression of RTK signaling, and suggests novel co-therapies to more effectively treat cancers driven by EML4-ALK and possibly other RTK fusions. Our work also demonstrates the potential of functional optogenetic profiling for drug discovery to promote cancer therapy. Citation Format: David Gonzalez-Martinez, Lee Roth, Thomas Mumford, Yael Mosse, Asmin Tulpule, Trever Bivona, Lukasz Jan Bugaj. Inhibition of RTK fusion condensates enhances signal perception and promotes drug tolerance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 848.
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Mehta, Anurag, and Ullas Batra. "Molecular epidemiological study of microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene using immunohistochemistry as a cost effective alternative to fluorescence in situ hybridization for Indian patients with adenocarcinoma lung." Asian Journal of Oncology 03, no. 01 (January 2017): 045–49. http://dx.doi.org/10.4103/asjo.asjo_116_16.
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Abstract Background: With fluorescence in situ hybridization (FISH) as the main-stay for the detection of anaplastic lymphoma kinase (ALK) rearrangements, the ALK Break Apart FISH Probe Kit has become a Food and Drug Association-approved companion diagnostic for targeted therapy with the ALK inhibitor crizotinib in lung cancers. The objective of this molecular epidemiological study was to estimate the prevalence of microtubule-associated protein-like 4-ALK (EML4-ALK) fusion gene using immunohistochemistry (IHC) as a cost effective alternative to FISH for Indian patients with nonsmall-cell cancer (NSCC)-adenocarcinoma, favor adenocarcinoma lung and NSCC- Not otherwise specified (NOS). Materials and Methods: Patients with NSCC-adenocarcinoma, favor adenocarcinoma lung, and nonsmall cell lung cancer-NOS histology were considered for this study. Permission was obtained from the Ethics Committee before the start of the study. Clinical characteristics and treatment details were collected from the patient's medical records. IHC analysis was performed using a Ventana automated immunostainer (Benchmark XT). Detection was performed using OptiView DAB Detection and Amplification Kit. Results: A total of 200 NSCC-adenocarcinoma, favour adenocarcinoma and NSCC-NOS patients were included in the study. There were 122 (61%) men and 78 (39%) women with a median age of 57 years. Of the 200 patients, 43 (21.5%) were nonsmokers and 175 (87.5%) had Stage-IV disease at the time of initial diagnosis. 48 (24%) cases were positive for epidermal growth factor receptor mutations, whereas EML4-ALK fusion gene was present in 27 (13.5%) patients. 25 of the 27 patients with ALK positivity received crizotinib therapy. Conclusions: The incidence of EML4-ALK gene fusions (13.5%) in this Indian population is four-fold high than the previous reported incidences and supports the claim of several recent studies that a relatively new ALK clone, 5A4, and D5F3 from Leica/Novocastra and cell signaling technology/Ventana, respectively can accurately identify ALK rearranged lung adenocarcinoma. The inclusion of IHC for the detection of EML4-ALK gene fusions as a low cost alternative seems justified in low resource setting.
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Xiang, Yan, Shiyu Zhang, Xiaoxu Fang, Yingying Jiang, Tingwen Fang, Jinwen Liu, and Kaihua Lu. "Therapeutic Advances of Rare ALK Fusions in Non-Small Cell Lung Cancer." Current Oncology 29, no. 10 (October 16, 2022): 7816–31. http://dx.doi.org/10.3390/curroncol29100618.
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Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is the leading cause of cancer-related death. Despite advances in chemotherapy and immunotherapy, the prognosis for advanced patients remains poor. The discovery of oncogenic driver mutations, such as anaplastic lymphoma kinase (ALK) mutations, means that a subset of patients has opportunities for targeted therapy. With the improvement of genetic testing coverage, more and more ALK fusion subtypes and ALK partners have been discovered, and more than 90 rare ALK fusion subtypes have been found in NSCLC. However, unlike the common fusion, echinoderm microtubule-associated protein-like 4 (EML4)-ALK, some rare ALK fusions such as striatin (STRN)-ALK and huntingtin interacting protein 1 (HIP1)-ALK, etc., the large-scale clinical data related to its efficacy are still immature. The clinical application of ALK-tyrosine kinase inhibitors (ALK-TKIs) mainly depends on the positivity of the ALK gene, regardless of the molecular characteristics of the fusion partner. Recent clinical studies in the ALK-positive NSCLC population have demonstrated differences in progression-free survival (PFS) among patients based on different ALK fusion subtypes. This article will introduce the biological characteristics of ALK fusion kinase and common detection methods of ALK fusion and focus on summarizing the differential responses of several rare ALK fusions to ALK-TKIs, and propose corresponding treatment strategies, so as to better guide the application of ALK-TKIs in rare ALK fusion population.
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Maus, Martin Karl Herbert, Craig Stephens, Gary Zeger, Peter Philipp Grimminger, and Eric Huang. "Identification of novel variant of EML4-ALK fusion gene in NSCLC: Potential benefits of the RT-PCR method." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e12007-e12007. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e12007.
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e12007 Background: The discovery of the transforming fusion gene of the anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein like 4 (EML4) as an oncogene in 2007 has led to its validation as a clinical target in NSCLC patients in a short period of time. The inhibition of the anaplastic lymphoma receptor tyrosine kinase has demonstrated to prolong progression-free survival compared to the standard of care chemotherapy in patients with advanced NSCLC that are ALK positive. However, the clinical implications of the 15 different variants of the EML4-ALK transforming gene described so far are currently not defined. Here we present a novel variant of the EML4-ALK fusion gene which we named variant 3c. Methods: RNA extracted from formalin fixed paraffin embedded (FFPE) specimens from patients with advanced and metastatic NSCLC was amplified, using primers and probes designed to detect specific EML4-ALK fusion gene fragments. Gel electrophoresis showed a different band for the new variant 3c compared to the known bands of positive cell lines for variant 3a and 3b. These findings were further investigated by dye-terminator Sequencing and FISH. Results: The novel variant, detected in two NSCLC specimens, is longer than v3a and shorter than v3b, representing an 18 base pair insertion of intron 19 of ALK between exon 6 of EML4 and exon 20 of ALK. All of the two samples showed exactly the same sequencing result. One of the samples was negative for FISH break apart testing and the other one showed a positive result, defined by ≥ 15% split nuclei as indicative of an ALK rearrangement. Conclusions: Compared to FISH technology, RT-PCR enables the detection of different isoforms of the EML4-ALK transforming gene, which can be validated by sequencing. Only one out of two samples that were positive for the new variant by RT-PCR could be confirmed by FISH. The clinical significance of the different variants, notably to resistance and response to ALK-Inhibitors and the concordance and sensitivity of FISH and RT-PCR should be subject to further investigations.
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Papageorgiou, Savvas, Sarah L. Pashley, Laura O’Regan, Sam Khan, Richard Bayliss, and Andrew M. Fry. "Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer." Cancers 14, no. 14 (July 15, 2022): 3452. http://dx.doi.org/10.3390/cancers14143452.
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EML4-ALK is an oncogenic fusion protein that accounts for approximately 5% of NSCLC cases. Targeted inhibitors of ALK are the standard of care treatment, often leading to a good initial response. Sadly, some patients do not respond well, and most will develop resistance over time, emphasizing the need for alternative treatments. This review discusses recent advances in our understanding of the mechanisms behind EML4-ALK-driven NSCLC progression and the opportunities they present for alternative treatment options to ALK inhibitor monotherapy. Targeting ALK-dependent signalling pathways can overcome resistance that has developed due to mutations in the ALK catalytic domain, as well as through activation of bypass mechanisms that utilise the same pathways. We also consider evidence for polytherapy approaches that combine targeted inhibition of these pathways with ALK inhibitors. Lastly, we review combination approaches that use targeted inhibitors of ALK together with chemotherapy, radiotherapy or immunotherapy. Throughout this article, we highlight the importance of alternative breakpoints in the EML4 gene that result in the generation of distinct EML4-ALK variants with different biological and pathological properties and consider monotherapy and polytherapy approaches that may be selective to particular variants.
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Hochmair, Maximilian J., Ulrike Setinek, Thomas Efstathiades, Klaus Kirchbacher, Andrea Mohn-Staudner, Britt-Madeleine Arns, Melina Gulesserian, et al. "EML4-ALK mutation in Austrian patients with NSCLC: A multicenter study." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e19093-e19093. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e19093.
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e19093 Background: EML4 (echinoderm microtubule-associated protein-like 4) - ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase, an oncoprotein found in a subgroup of non-small-cell lung cancer (NSCLC) predicts the response to ALK inhibitors. In general, AML4-ALK mutation is found in 2 to 7% of Caucasian patients with NSCLC and occurs more often in never and former smokers, adenocarcinomas, and younger, male patients. However, the frequency of EML4-ALK mutation in Austrian patients with NSCLC is unknown. The aim of the study was to evaluate the prevalence of EML4-ALK mutation in Austrian patients with NSCLC. Methods: From September 2011 to October 2012 tumour tissue from bronchoscopy, CT- and ultrasound guided biopsies and surgical specimen with histological type of adenocarcinoma and NSCLC NOS (Not Otherwise Specified) excluding squamous cell carcinoma, large cell carcinoma and neuroendocrine carcinoma were analysed for EML4-ALK mutations from 4 hospitals in Austria with high expertise in the management of lung cancer. Mutation detection was performed with a two-step procedure. First an immunhistochemical staining was done (ALK confirm/Ventana) and further on positive cases were tested by ALK FISH (dual colour breakapart FISH/Abbott Vysis). Results: In total 639 patients were analysed. EML4-ALK positive immunohistochemical staining was found in 35 patients (5,48%). 14 of these patients (2,19%) showed positive ALK FISH analysis. Conclusions: Frequency of EML-ALK mutations in Austrian patients with NSCLC was similar to other Caucasian peers.
Book chapters on the topic "EML4-ALK fusion protein"
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Kerr, David J., Daniel Haller, and Jaap Verweij. "Principles of chemotherapy." In Oxford Textbook of Cancer Biology, edited by Francesco Pezzella, Mahvash Tavassoli, and David J. Kerr, 413–22. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780198779452.003.0028.
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Systemic cancer treatment stems initially from empirically discovered DNA synthesis inhibitors, which either deplete the cell of nucleotides, induce cross-link, or cause DNA single and double strand breaks or impair the cellular machinery of DNA repair, using mechanistically diverse drugs. A period of enlightenment followed, with anticancer drug development driven by an increased understanding of enzymes and pathways involved in cell signalling, control of angiogenesis, and epigenetics. This provided a parallel path towards precision cancer medicine where specific drugs can be targeted to patients with particular mutations. These include point mutations in RAS, which are used to exclude colorectal cancer patients from being treated with epidermal growth factor inhibitors; chromosomal translocations encoding fusion proteins which are cancer specific and serve as novel drug targets (e.g. BCR/ABL and imatinib, or EML4-ALK fusion oncogene and crizotinib). More recently, there has been a reanimation of immune approaches to cancer therapy with the clinical introduction of immune checkpoint inhibitors, designer T cells, and patient-specific antitumour vaccines. What next? It may be that next-generation sequencing provides an endless stream of so-called actionable mutations that permits tailored application of mutation-specific drugs, but so far there is little evidence of clinical benefit from such therapies.
Conference papers on the topic "EML4-ALK fusion protein"
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Vázquez, Ramiro, Lucile Astorgues-Xerri, Mohamed Bekradda, Esteban Cvitkovic, Patrice Herait, Michela Boi, Giorgio Inghirami, Maurizio D'Incalci, María E. Riveiro, and Eric Raymond. "Abstract 5530: OTX015, a novel pan BET-BRD inhibitor is active in non-small-cell lung cancer (NSCLC) cell lines bearing the fusion protein EML4-ALK." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-5530.
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