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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.
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Heuckmann, Johannes M., Hyatt Balke-Want, Florian Malchers, Martin Peifer, Martin L. Sos, Mirjam Koker, Lydia Meder, et al. "Differential Protein Stability and ALK Inhibitor Sensitivity of EML4-ALK Fusion Variants." Clinical Cancer Research 18, no. 17 (August 21, 2012): 4682–90. http://dx.doi.org/10.1158/1078-0432.ccr-11-3260.
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Hsiao, Sheng-Yen, Hong-Lin He, Teng-Song Weng, Cheng-Yao Lin, Chien-Ming Chao, Wen-Tsung Huang, and Chao-Jung Tsao. "Colorectal Cancer with EML4-ALK Fusion Gene Response to Alectinib: A Case Report and Review of the Literature." Case Reports in Oncology 14, no. 1 (March 1, 2021): 232–38. http://dx.doi.org/10.1159/000511069.
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Anti-epithelial growth factor receptor or anti-vascular endothelial growth factor agents combined with chemotherapy were the standard of treatment for metastatic colorectal cancer (CRC). However, increasing evidence of molecularly stratified treatment makes the complexity of treatment. Anaplastic lymphoma kinase (ALK) gene alternation is one of potential target for biomarker-guided therapy for CRC. We present a case of a 56-year-old man who suffered from advanced ascending colon cancer, harboring echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion gene E21; A20 variant, a rare variant in EML4-ALK fusion gene in lung cancer. We also detected this fusion gene from different tissue types including circulating tumor DNA (ctDNA) and ascites fluid. The patient was offered alectinib, an ALK inhibitor, with partial response in lung, liver, and peritoneal metastasis for 8 months. Tumor heterogeneity, especially in gastrointestinal tract cancer, raise our interest in comprehensive genetic profiling in clinical practice. Convenience and reliability of next-generation sequencing, including using ctDNA, help physicians deal with clinical dilemma. ALK-positive CRC is rare. However, advanced CRC with ALK gene alteration responds to ALK inhibitor. It is reasonable to check ALK gene alteration in clinical practice for CRC.
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Wangsiricharoen, Sintawat, Minghao Zhong, Sarangarajan Ranganathan, Andres Matoso, and Pedram Argani. "ALK-rearranged Renal Cell Carcinoma (RCC): A Report of 2 Cases and Review of the Literature Emphasizing the Distinction Between VCL-ALK and Non-VCL-ALK RCC." International Journal of Surgical Pathology 29, no. 7 (March 17, 2021): 808–14. http://dx.doi.org/10.1177/10668969211003660.
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Anaplastic lymphoma kinase (ALK) rearrangement-associated renal cell carcinoma ( ALK-rearranged RCC) is a new provisional entity that has been included in the 2016 World Health Organization classification of RCCs. We report 2 cases of ALK-rearranged RCC, 1 with a vinculin-ALK ( VCL-ALK) fusion and the other with an EML4-ALK fusion. The VCL-ALK RCC occurred in a 14-year-old girl with sickle cell trait and showed features similar to previously described VCL-ALK RCCs, including medullary epicenter, solid architecture, and polygonal cells with cytoplasmic vacuoles. The EML4-ALK RCC occurred in a 14-year-old boy with no evidence of sickle cell trait and had multiple less-specific growth patterns comprising tubular, solid, and tubulopapillary architectures in the desmoplastic stroma, reminiscent of collecting duct carcinoma. Both tumors demonstrated cytoplasmic and membranous ALK protein expression by immunohistochemistry. Fluorescence in situ hybridization confirmed the ALK gene rearrangements in both cases. On review in the literature, we found that solid architecture and cytoplasmic vacuoles were present significantly more frequently in VCL-ALK RCC than in non- VCL-ALK RCC, supporting the distinctive nature of the former.
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Campos-Gomez, Saul, Humberto Lara-Guerra, Mark J. Routbort, Xinyan Lu, and George R. Simon. "Lung adenocarcinoma with Concurrent KRAS Mutation and ALK Rearrangement Responding to Crizotinib: Case Report." International Journal of Biological Markers 30, no. 2 (April 2015): 254–57. http://dx.doi.org/10.5301/jbm.5000127.
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Chromosomal translocation resulting in the fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase ( ALK) gene was recently identified as a novel genetic alteration in a subset of non-small cell lung cancer (NSCLC). EML4– ALK translocations are rare events associated with specific clinicopathological features, such as never or light smoking history, young age and adenocarcinoma with signet ring or acinar histology. Reports suggest ALK gene arrangements are mutually exclusive with EGFR and KRAS mutations. To the best of to our knowledge, this is the first case report of a patient with concurrent KRAS mutation and ALK translocation. This patient had an excellent response to crizotinib, suggesting that the ALK translocation was the oncogenic driver.
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Batra, Ullas, Mohit Aggarwal, Parveen Jain, Pankaj Goyal, Abhishek Yadav, Udip Maheshwari, and Anurag Mehta. "Clinical outcome study of crizotinib in immunohistochemistry-proven echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene among Indian patients with adenocarcinoma lung." South Asian Journal of Cancer 07, no. 01 (January 2018): 61–64. http://dx.doi.org/10.4103/sajc.sajc_215_17.
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Abstract Aims: The anaplastic lymphoma kinase (ALK) Break Apart FISH Probe Kit and Ventana anti-ALK (D5F3) CDx immunohistochemistry (IHC) assay are the Food and Drug Administration-approved companion diagnostic for targeted therapy with the ALK inhibitor crizotinib in lung cancers. The aim of this study was to assess the efficacy and safety of twice daily crizotinib tablet (250 mg) in IHC-proven echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene among Indian patients with adenocarcinoma lung in the routine clinical practice. Subjects and Methods: Patients with nonsmall cell lung cancer (NSCLC), adenocarcinoma histology, whose tumors were found to be positive for EML4-ALK fusion gene using IHC, were considered for this study. 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 25 NSCLC adenocarcinoma patients were included in the study. There were 14 (56%) women and 10 (44%) men with a median age of 53 years. All patients had Stage IV disease at the time of initiation of crizotinib therapy. One patient achieved complete response and 20 achieved response rate (PR) for an overall PR of 84%. The median progression-free survival (PFS) was 11.8 months and median overall survival (OS) was 20.6 months. Two (8%) patients experienced severe hepatotoxicity requiring permanent discontinuation of crizotinib therapy. Conclusions: A very high PR, PFS, and OS achieved in our study population indicates that IHC can accurately identify EML4 ALK fusion gene mutations in lung adenocarcinoma patients who are responsive to ALK inhibitors such as crizotinib. IHC should be considered as a cost-effective alternative to FISH, especially in low-resource countries.
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Hui, Beina, Jingping Zhang, Xiaobo Shi, Fangfang Xing, Yang W. Shao, Yuanyuan Wang, Xiaozhi Zhang, and Shuwen Wang. "EML4-ALK, a potential therapeutic target that responds to alectinib in ovarian cancer." Japanese Journal of Clinical Oncology 50, no. 12 (August 26, 2020): 1470–74. http://dx.doi.org/10.1093/jjco/hyaa156.
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Abstract Ovarian cancer is prone to recurrence and chemotherapy resistance. Ovarian tumours of some patients have been positive for anaplastic lymphoma kinase fusion gene expression (ALK+). Preclinical studies indicate that anaplastic lymphoma kinase inhibitor can suppress the growth of ovarian cancer cells and transplantation tumours. Here, we present a patient with metastatic ALK+ high-grade serous ovarian cancer that testing positive for EML4-ALK (microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase gene), experienced dramatic benefit after administration of the anaplastic lymphoma kinase inhibitor alectinib. This is the first clinical evidence that treatment with alectinib may provide a personalized maximum benefit for patients with high-grade serous ovarian cancer who are positive for EML4-ALK.
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Sugiyama, Keiji, Ai Izumika, Akari Iwakoshi, Riko Nishibori, Mariko Sato, Kazuhiro Shiraishi, Hiroyoshi Hattori, Rieko Nishimura, and Chiyoe Kitagawa. "Successful Alectinib Treatment for Carcinoma of Unknown Primary with EML4-ALK Fusion Gene: A Case Report." Current Oncology 28, no. 3 (May 21, 2021): 1938–45. http://dx.doi.org/10.3390/curroncol28030180.
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Gene alteration in anaplastic lymphoma kinase (ALK) is rare, and the efficacy of ALK inhibitors in the treatment of carcinoma of unknown primary (CUP) with ALK alteration remains unclear. The patient was a 56-year-old woman who presented with cervical lymph node swelling. Computed tomography revealed paraaortic, perigastric, and cervical lymph node swelling; ascites; a liver lesion; and a left adrenal mass. A cervical lymph node biopsy was performed, and pathological diagnosis of an undifferentiated malignant tumor was conducted. Finally, the patient was diagnosed with CUP and treated with chemotherapy. To evaluate actionable mutations, we performed a multigene analysis, using a next-generation sequencer (FoundationOne® CDx). It revealed that the tumor harbored an echinoderm microtubule-associated protein-like 4 (EML4) and ALK fusion gene. Additionally, immunohistochemistry confirmed ALK protein expression. Alectinib, a potent ALK inhibitor, was recommended for the patient at a molecular oncology conference at our institution. Accordingly, alectinib (600 mg/day) was administered, and the multiple lesions and symptoms rapidly diminished without apparent toxicity. The administration of alectinib continued for a period of 10 months without disease progression. Thus, ALK-tyrosine kinase inhibitors should be considered in patients with CUP harboring the EML4-ALK fusion gene.
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Shafik, Hanan Ezzat, and Mohamed Ashour. "Frequency of EGFR Mutation and EML4-ALK fusion gene in Arab Patients with Adenocarcinoma of the Lung." Forum of Clinical Oncology 6, no. 2 (June 1, 2015): 19–23. http://dx.doi.org/10.1515/fco-2015-0009.
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Abstract Introduction: Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. The frequency of epidermal growth factor receptor (EGFR) mutations is ethnicity-dependent, with a higher proportion in Asian populations than in whites, while the incidence of EML4-ALK (echinoderm microtubule-associated-protein like 4-anaplastic lymphoma kinase) fusion gene ranged from 1.6% to 16.4% in patients with NSCLC and these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. This study was conducted to determine the frequency of EGFR mutation and EML4-ALK fusion gene in our population and to determine the effect of different clinicopathological features on the expression of those mutations in patients with lung adenocarcinoma. Results: EGFR mutations were detected in approximately 33% of our patients in this series; the most frequently detected mutation was exon 19 deletion. EML4-ALK fusion gene was detected in 7.3% of patients. Conclusion: Our population exhibited the incidence of EGFR mutation approximately similar to that reported in East Asia and Japanese patients, higher than that recorded in USA, and Australia. However, more studies with larger patients’ numbers are needed to verify this finding.
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Huo, Yinping, Tangfeng Lv, Mingxiang Ye, Suhua Zhu, Jiaxin Liu, Hongbing Liu, and Yong Song. "F-circEA1 regulates cell proliferation and apoptosis through ALK downstream signaling pathway in non-small cell lung cancer." Human Cell 35, no. 1 (October 11, 2021): 260–70. http://dx.doi.org/10.1007/s13577-021-00628-7.
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AbstractStudies have confirmed that circular RNA (circRNA) has a stable closed structure, which plays an important role in the progression of tumors. Cancers with positive fusion genes can produce associated fusion circRNA (F-cirRNA). However, there are no reports concerning a role for F-circRNA of the echinoderm microtubule associated-protein like 4-anaplastic lymphoma kinase variant 1 (EML4-ALK1) in non-small cell lung cancer (NSCLC). Our study confirmed the existence of fusion circEA1 (F-circEA1) in NCI-H3122 cells (carrying the EML4-ALK1 gene), F-circEA1 was expressed both in the cytoplasm and nucleus as determined by fluorescence in situ hybridization (FISH) and Sanger sequencing. CCK8 and transwell assays showed that F-circEA1 was beneficial to cell proliferation, metastasis, and invasion. Overexpression of F-circEA1 can also promote cell proliferation, migration and invasion in A549 and SPCA1 cells (non-small cell lung cancer cell line not carrying the EML4-ALK1 gene). Interference with F-circEA1, induced cell cycle arrest and promoted apoptosis as determined by flow cytometry, and increased drug sensitivity to crizotinib in H3122 cells. F-circEA1 directly affected the expression of parental gene EML4-ALK1. Further research found that F-circEA1 can affect the downstream signaling pathway of ALK. In vivo, the growth rate of xenogeneic tumors was reduced and the protein expression level of EML4-ALK1 was significantly decreased in transplanted tumors measured by immunohistochemistry (IHC) after interference with F-circEA1. In conclusion, F-circEA1 can be considered as a proto-oncogene that regulates cell proliferation and apoptosis by affecting the expression of the parental gene EML4-ALK1 and its ALK downstream signaling pathway in non-small cell lung cancer.
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Hu, Wanming, Li Yuan, and Jing Zeng. "PATH-01. Infant-Type Hemispheric Glioma: New Molecular Alterations and Precision-Medicine Treatment." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i157—i158. http://dx.doi.org/10.1093/neuonc/noac079.585.
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Abstract BACKGROUND: Infant-type hemispheric glioma, harboring alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET, is a new subtype of Pediatric-type diffuse high-grade gliomas in the 2021 WHO classification of CNS tumors. It has important clinical therapeutic value with specialized therapeutic drugs. Here, we presented 3 cases of infant-type hemispheric glioma. Patient1 with EML4-ALK fusion which often appeared in lung cancer, the other 2 patients have new molecular alterations which has not been reported before (Patient2 has both NTRK1-TP53/TP53-NTRK1 fusions and p53 protein showed characteristic cytoplasm positive; Patient3 presented a brand-new ALK-QKI fusion combined with ALK mutation and focal SMARCB1 deletion. All these 3 cases received corresponding targeted therapy and have a good recovery and normal neurologic function till now. METHOD: Immunohistochemistry, fluorescent in situ hybridization and whole-transcriptome sequencing. RESULTS: Case 18 months, male, right semiovale center occupation. Histopathology: High-grade neuroepithelial neoplasm. IHC: GFAP(only few cells+), Olig2(-), S100(+), CD56(+), Syn(-), NSE(focal+), NeuN(-), CD34(-), INI-1(+), Ki67(10%+). Characteristic Molecular Information: EML4-ALK fusion. Follow-up: 15 months, alive. Case 2: 3 years, female, insular lobe occupation.Histopathology: Gliosarcoma. IHC: GFAP(partly+), Olig2(partly+), Vimentin(+), P53(cytoplasm+), pan-TRK(+), Ki67(25%+). Reticular fiber staining showed biphasic tissue pattern with reticulin-rich sarcomatous and reticulin-free gliomatous elements. Characteristic Molecular Information: NTRK1-TP53 and TP53-NRTK1 fusion. Follow-up: 27 months, alive. Case 3: 3 years, male, left parietal occipital lobe occupation. Histopathology: GBM and AT/RT. IHC: GFAP(partly+), Olig2(partly+), INI-1(partly-), BRG1(+), SYN(-), CD34(-), BRAF(-), S100(-), CK(-), H3K27M(-), IDH1(-), P53(40%+), ATRX(+), pan-TRK(-), ALK(+), Ki67(30%+). Characteristic Molecular Information: ALK mutation, ALK-QKI fusion, RAD51C mutation and focal SMARCB1(INI-1) deletion. Follow-up: 14 months, alive. CONCLUSION: Infant-type hemispheric glioma is a special kind of glioma, which is particularly suitable for precision-medicine treatment approaches. Their overall survival is good compared with other three pHGG subtype.
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Kimura, Tatsuo, Junko Sowa-Osako, Toshiyuki Nakai, Ayako Ohyama, Tomoya Kawaguchi, Daisuke Tsuruta, Masahiko Ohsawa, and Kazuto Hirata. "Alectinib-Induced Erythema Multiforme and Successful Rechallenge with Alectinib in a Patient with Anaplastic Lymphoma Kinase-Rearranged Lung Cancer." Case Reports in Oncology 9, no. 3 (December 8, 2016): 826–32. http://dx.doi.org/10.1159/000453314.
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Background: Alectinib is an oral drug developed for the treatment of patients with fusion gene encoding echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-rearranged non-small cell lung cancer (NSCLC). Here, we present the case of a patient treated with alectinib who developed a hypersensitivity reaction with successful rechallenge treatment. Case Presentation: A 39-year-old woman who was a passive smoker was referred to Osaka City University Hospital for the evaluation of a skin event caused by treatment for NSCLC with the fusion gene EML4-ALK. The skin reaction was observed on the anterior chest, upper arms, and ear auricles on day 11 of treatment with oral alectinib. The skin event presented as widely distributed erythematous macules that were confluent, indicating a severe and life-threatening form. The skin lesions started to resolve after the initiation of treatment with 40 mg prednisolone. After regrowth of the tumor, she received a rechallenge program for alectinib for 2 weeks; thereafter, alectinib treatment was successfully reinitiated. Conclusion: To the best of our knowledge, we present the first case in which alectinib, which binds to the adenosine triphosphate site of EML4-ALK, induced erythema multiforme. Moreover, successful readministration of alectinib through our rechallenge program has not been reported so far.
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Shin, Miyoung, Paris Petersen, Steven Lau-Rivera, Segun Jung, Sally Agersborg, Jacyln Hechtman, Fernando Lopez-Diaz, and Vincent Funari. "Abstract 1254: Actionable fusions detected by RNA-seq co-occur with PD-L1 expression and driver mutations in solid tumors patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1254. http://dx.doi.org/10.1158/1538-7445.am2022-1254.
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Abstract Background: Incorporating gene fusions into a comprehensive profile is critical not only because very effective therapies targeting oncogenic fusion proteins exist but they may also negate the response to therapy of an actionable SNV and InDel mutations. We examined the co-occurrence of actionable gene fusions detected by RNA-seq with actionable SNVs/InDels and with the immunotherapy response biomarker, PD-L1. Methods: In 2021, 5341 FFPE samples were analyzed by our clinical laboratory using a novel hybridization-based RNA sequencing assay. DNA (SNV/Indels) mutations were detected with a clinical grade NGS assay and PD-L1 protein expression was determined by IHC using an appropriate LDT or FDA approved assay. De-identified data were analyzed following an approved IRB protocol. Results: Of the 5341 patients tested for gene fusions only 0.7% were profiled with a comprehensive fusion detection panel for 250 clinically relevant fusion genes. Conversely, 67% of all patients were tested only for NTRK gene fusions. The prevalence of the following most relevant fusions was: ALK=3.16% (in particular EML4-ALK), NTRKs=0.85%, FGFR2=5.60%, RET=1.34% and ROS1=1.05%. Among NTRK fusions, NTRK3 was detected in 52.9% of the positive cases; in particular, dominant fusions are ETV6-NTRK3 (26%) and EML4-NTRK3 (20%). In the 163 fusion positive cases, 37 cases had available DNA mutation testing and PD-L1 expression testing. These patients presented 24 different actionable fusions, including ALK (2), FGFR1/2 (5), NTRK 1/2/3 (10), NRG1 (3), RET (3), and ROS1 (3) fusions. Interestingly, while 73% (27/37) of those tumors were PD-L1 positive, similar to the 75% found on the fusion negative samples, PD-L1 was positive in 88% (15/17) of the lung samples with pathogenic mutations from this subset. This was strikingly higher than the 45% (192/424) found in the fusion negative cohort. Finally, excluding TP53 mutations, NTRK fusions frequently co-occurred with RNF43, FBXW7, TERT promoter, and ARID1A pathogenic mutations. FGFR fusions co-occurred with BAP1, PBRM1, or KRAS mutations, which correlates with the fact that both FGFR2 fusions and swi/snf alterations are enriched in intrahepatic cholangiocarcinoma, where the FGFR fusions were detected. RET fusions co-occurred with ARID1A and TERT. ROS1 fusions co-occurred with SMARCA4 and KRAS pathogenic mutations simultaneously. NRG1 fusions co-occurred with ARID1A and FBXW7 mutations. EML4-ALK fusions co-occurred with FGFR2 and KMT2D variants of unknown significance. Conclusion: Actionable cancer-driving gene fusions were detected by RNA-sequencing and co-occurred with other biomarkers that can guide the selection of therapies, such as immune checkpoint inhibitors (ICI) and olaparib. The data suggest that gene fusion testing is an important addition to the genomic profiling for therapy selection in solid tumors. Citation Format: Miyoung Shin, Paris Petersen, Steven Lau-Rivera, Segun Jung, Sally Agersborg, Jacyln Hechtman, Fernando Lopez-Diaz, Vincent Funari. Actionable fusions detected by RNA-seq co-occur with PD-L1 expression and driver mutations in solid tumors patients [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 1254.
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Luo, Lian-Xiang, Ying Li, Yu-Zhen Niu, Yu-Wei Wang, Qian-Qian Wang, Xing-Xing Fan, Jia-Hui Xu, Liang Liu, Elaine Lai-Han Leung, and Xiao-Jun Yao. "Identification of a potent kinase inhibitor targeting EML4-ALK fusion protein in non-small cell lung cancer." MedChemComm 8, no. 10 (2017): 1914–18. http://dx.doi.org/10.1039/c7md00305f.
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Wang, Dandan, Daixi Li, Guangrong Qin, Wen Zhang, Jian Ouyang, Menghuan Zhang, and Lu Xie. "The Structural Characterization of Tumor Fusion Genes and Proteins." Computational and Mathematical Methods in Medicine 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/912742.
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Chromosomal translocation, which generates fusion proteins in blood tumor or solid tumor, is considered as one of the major causes leading to cancer. Recent studies suggested that the disordered fragments in a fusion protein might contribute to its carcinogenicity. Here, we investigated the sequence feature near the breakpoints in the fusion partner genes, the structure features of breakpoints in fusion proteins, and the posttranslational modification preference in the fusion proteins. Results show that the breakpoints in the fusion partner genes have both sequence preference and structural preference. At the sequence level, nucleotide combination AG is preferred before the breakpoint and GG is preferred at the breakpoint. At the structural level, the breakpoints in the fusion proteins prefer to be located in the disordered regions. Further analysis suggests the phosphorylation sites at serine, threonine, and the methylation sites at arginine are enriched in disordered regions of the fusion proteins. Using EML4-ALK as an example, we further explained how the fusion protein leads to the protein disorder and contributes to its carcinogenicity. The sequence and structural features of the fusion proteins may help the scientific community to predict novel breakpoints in fusion genes and better understand the structure and function of fusion proteins.
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Singh, Randeep, and Nitesh Rohtagi. "Clinicopathological and molecular epidemiological study of lung cancer patients seen at a tertiary care hospital in Northern India." South Asian Journal of Cancer 06, no. 04 (October 2017): 171–75. http://dx.doi.org/10.4103/sajc.sajc_63_17.
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Abstract Aims: The primary objective of this study was to estimate the clinicopathological and molecular profile of lung cancer patients along with the evaluation of their clinical characteristics at a tertiary care hospital in Northern India. Subjects and Methods: A total of 421 patients with lung cancer histology who were treated at Max Super Speciality Hospitals were included in the study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and permission was obtained from the Ethics Committee before the start of the study. Clinical characteristics and molecular profiling data were collected from the patient's medical records. Results: There were 330 (78.4%) men and 91 (21.6%) women with a median age of 62 years (range: 30–93 years). Of the 421 patients, 388 (92.2%) patients had the nonsmall cell lung cancer (NSCLC) histology whereas 33 (7.8%) patients were of SCLC histology. Histology and gender had a significant association with NSCLC and SCLC (P < 0.05). Epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene testing was done in 120 and 93 patients, respectively. Of the 120 patients, 24 (20%) cases were positive for EGFR mutations whereas EML4-ALK fusion gene was present in 8 (8.6%) out of 93 patients. Conclusions: Our study confirms the importance of molecular testing in the NSCLC patient subgroup with an aim to identify the exact molecular targets that can benefit from the newer generation of targeted therapies.
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Miller, Jill, Zhihua Peng, Rebecca Wilcox, Mark Evans, Kumarasen Cooper, Steven Ades, and Claire F. Verschraegen. "Investigation of anaplastic lymphoma kinase (ALK) translocations in gastric and esophageal signet ring cell carcinomas." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e15106-e15106. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e15106.
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e15106 Background: Anaplastic lymphoma kinase (ALK) fusion oncogenes are present in multiple cancer types. The inversion of echinoderm microtubule associated protein like 4 (EML4) and ALK genes on chromosome 2 is present in a subset of non-small cell lung cancer (NSCLC) patients. ALK mutated lung cancers demonstrate a significantly higher incidence of signet ring cell histology than compared to ALK-negative tumors. Based on the histological similarities of ALK positive NSCLC and signet ring cell carcinomas (SRCC) of the GI tract, we hypothesized that gastric and/or esophageal SRCC may also harbor ALK translocations. Methods: Thirty-five formalin-fixed, paraffin-embedded (FFPE) tissue specimens of SRCC originating from esophageal, GE junction or gastric locations were obtained from the Fletcher Allen Healthcare (Burlington, Vermont) tissue bank following Internal Review Board guidelines. Confirmation of SRCC or adenocarcinoma with signet ring cell features was confirmed by a board certified, gastrointestinal pathologist. SRCC specimens were analyzed by fluorescence in situ hybridization (FISH) analysis using an ALK (2p23) break-apart probe (Kreatech Diagnostics). Results: The FISH analysis revealed no evidence of ALK translocation: all thirty-five (100%) SRCC specimens showed intact (yellow) ALK FISH signals. Conclusions: These data indicate that despite histological similarities between SRCC of the GI tract and ALK positive NSCLC, ALK translocations are unlikely to be a significant contributor to gastric and esophageal SRCC molecular etiology. Further genomic investigations are on-going. This study was performed with funding received from the Lake Champlain Cancer Research Organization.
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Wang, Wen Xian, Chun-Wei Xu, Ziming Li, Zhengbo Song, Wenfeng Fang, Liyun Miao, You-Cai Zhu, et al. "Chinese advanced fusion-dependent lung cancer patients: Molecular spectrum and treatment options using next generation sequencing—A multicenter study (Yangtze River Delta Lung Cancer Cooperation Group-001)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e21036-e21036. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21036.
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e21036 Background: Lung cancer with drug receptor protein kinase fusion is regarded as a large class of molecular event, which is called fusion-dependent lung cancer. Fusion-dependent lung cancer accounts for about 10%-15% of non-small cell lung cancer. Therefore, the identification and detection of fusion-dependent lung cancer patients are very important in China. Here we reported a total of 4111 patients with Chinese fusion-dependent lung cancer. Methods: A multicenter study in China was initiated from Dec. 2019, and lung patients have been enrolled as of Dec. 2020. A total of 4111 patients with fusion-dependent were analyzed based on medical records and detailed patient questionnaires. Results: Of this entire cohort, 4111 patients were identified with fusion-dependent, including ALK fusions (2190, 53.27%), ROS1 fusions (894, 21.75%), RET fusions (521, 12.67%), NTRK fusions (128, 3.11%), FGFR fusions (84, 2.04%), NRG1 fusions (41, 1.00%), ERBB2 fusions (55, 1.34%), BRAF fusions (44, 1.07%), MET fusions (34, 0.83%), EGFR fusions (74, 1.80%), Other fusions (46, 1.12%). In ALK fusions, there were 1856 cases (84.75%) of EML4-, including A20(94.64%) and non-A20(5.36%), and other partners STRN-, KIF5B-, HIP1-, KLCl-, successively; In ROS1 fusions, there were 461 cases (51.57%) of CD74-, and other partners EZR-, SDC4-, SLC34A2-, TPM3-, GOPC-, successively; In RET fusions, there were 329 cases (63.15%) of KIF5B-, and other partners CCDC6-, NCOA4-, ERC1-, successively; In NTRK fusions, there were 22 cases (17.19%) of TPM3-NTRK1, and other types ETV6-NTRK3, LMNA-NTRK1, AGTPBP1-NTRK2 successively; In FGFR fusions, there were 40 cases (47.61%) of FGFR3-TACC3, and other types FGFR2-TACC2, ATE1-FGFR2, BAG4-FGFR1, successively; In NRG1 fusions, there were 11 cases (26.83%) of CD74-, and other partners SDC4-, RBPMS-, successively; In MET fusions, there were 9 cases (26.47%) of CD74-, and other partners HLA-DRB1-, KIF5B-, successively; In ERBB2, BRAF and EGFR fusions, the partners were scattered. And 3643 patiens (88.68%) of the detection were used DNA-based NGS, and Others were used RNA-based NGS. Patients with ALK and ROS1 fusions were routinely treated with targeted therapy. Patients with RET, NTRK, FGFR and NRG1 fusions were actively enrolled in the clinical trial. Patients with ERBB2, BRAF, MET and EGFR fusions were only treated with end-line trial target therapy, and they were eager to be included in the corresponding clinical trials. Conclusions: The common fusions of ALK, ROS1, RET are routine standardized treatment is very important. Although fusions are rare, it can not be ignored. Morever, these patients are eager to receive active targeted therapy. DNA+RNA based NGS is not widely used in China, but it is of great value to detect fusions, especially rare fusions, which is the future development trend.
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Sozzi, G., M. P. Martelli, D. Conte, P. Modena, V. Pettirossi, S. A. Pileri, and B. Falini. "The EML4-ALK transcript but not the fusion protein can be expressed in reactive and neoplastic lymphoid tissues." Haematologica 94, no. 9 (September 1, 2009): 1307–11. http://dx.doi.org/10.3324/haematol.2009.008045.
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Rybarczyk-Kasiuchnicz, Agnieszka, Rodryg Ramlau, and Katarzyna Stencel. "Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma." International Journal of Molecular Sciences 22, no. 2 (January 8, 2021): 593. http://dx.doi.org/10.3390/ijms22020593.
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Lung cancer is one of the most common malignant neoplasms. As a result of the disease’s progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies—neurosurgery and radiation therapy—do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)—activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes its dimerization and the activation of the intracellular signaling cascade. Signal transduction involves the activation of MAPK, AKT, and JNK, resulting in DNA synthesis and cell proliferation. In cancer cells, binding the ligand to the EGFR also leads to its dimerization and transduction of the signal to the cell interior. It has been demonstrated that activating mutations in the gene for EGFR-exon19 (deletion), L858R point mutation in exon 21, and mutation in exon 20 results in cancer cell proliferation. Continuous stimulation of the receptor inhibits apoptosis, stimulates invasion, intensifies angiogenesis, and facilitates the formation of distant metastases. As a consequence, the cancer progresses. These activating gene mutations for the EGFR are present in 10–20% of lung adenocarcinomas. Approximately 3–7% of patients with lung adenocarcinoma have the echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion gene. The fusion of the two genes EML4 and ALK results in a fusion gene that activates the intracellular signaling pathway, stimulates the proliferation of tumor cells, and inhibits apoptosis. A new group of drugs—small-molecule tyrosine kinase inhibitors—has been developed; the first generation includes gefitinib and erlotinib and the ALK inhibitor crizotinib. These drugs reversibly block the EGFR by stopping the signal transmission to the cell. The second-generation tyrosine kinase inhibitor (TKI) afatinib or ALK inhibitor alectinib block the receptor irreversibly. Clinical trials with TKI in patients with non-small cell lung adenocarcinoma with central nervous system (CNS) metastases have shown prolonged, progression-free survival, a high percentage of objective responses, and improved quality of life. Resistance to treatment with this group of drugs emerging during TKI therapy is the basis for the detection of resistance mutations. The T790M mutation, present in exon 20 of the EGFR gene, is detected in patients treated with first- and second-generation TKI and is overcome by Osimertinib, a third-generation TKI. The I117N resistance mutation in patients with the ALK mutation treated with alectinib is overcome by ceritinib. In this way, sequential therapy ensures the continuity of treatment. In patients with CNS metastases, attempts are made to simultaneously administer radiation therapy and tyrosine kinase inhibitors. Patients with lung adenocarcinoma with CNS metastases, without activating EGFR mutation and without ALK rearrangement, benefit from immunotherapy. This therapeutic option blocks the PD-1 receptor on the surface of T or B lymphocytes or PD-L1 located on cancer cells with an applicable antibody. Based on clinical trials, pembrolizumab and all antibodies are included in the treatment of non-small cell lung carcinoma with CNS metastases.
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Rybarczyk-Kasiuchnicz, Agnieszka, Rodryg Ramlau, and Katarzyna Stencel. "Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma." International Journal of Molecular Sciences 22, no. 2 (January 8, 2021): 593. http://dx.doi.org/10.3390/ijms22020593.
Full textAbstract:
Lung cancer is one of the most common malignant neoplasms. As a result of the disease’s progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies—neurosurgery and radiation therapy—do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)—activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes its dimerization and the activation of the intracellular signaling cascade. Signal transduction involves the activation of MAPK, AKT, and JNK, resulting in DNA synthesis and cell proliferation. In cancer cells, binding the ligand to the EGFR also leads to its dimerization and transduction of the signal to the cell interior. It has been demonstrated that activating mutations in the gene for EGFR-exon19 (deletion), L858R point mutation in exon 21, and mutation in exon 20 results in cancer cell proliferation. Continuous stimulation of the receptor inhibits apoptosis, stimulates invasion, intensifies angiogenesis, and facilitates the formation of distant metastases. As a consequence, the cancer progresses. These activating gene mutations for the EGFR are present in 10–20% of lung adenocarcinomas. Approximately 3–7% of patients with lung adenocarcinoma have the echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion gene. The fusion of the two genes EML4 and ALK results in a fusion gene that activates the intracellular signaling pathway, stimulates the proliferation of tumor cells, and inhibits apoptosis. A new group of drugs—small-molecule tyrosine kinase inhibitors—has been developed; the first generation includes gefitinib and erlotinib and the ALK inhibitor crizotinib. These drugs reversibly block the EGFR by stopping the signal transmission to the cell. The second-generation tyrosine kinase inhibitor (TKI) afatinib or ALK inhibitor alectinib block the receptor irreversibly. Clinical trials with TKI in patients with non-small cell lung adenocarcinoma with central nervous system (CNS) metastases have shown prolonged, progression-free survival, a high percentage of objective responses, and improved quality of life. Resistance to treatment with this group of drugs emerging during TKI therapy is the basis for the detection of resistance mutations. The T790M mutation, present in exon 20 of the EGFR gene, is detected in patients treated with first- and second-generation TKI and is overcome by Osimertinib, a third-generation TKI. The I117N resistance mutation in patients with the ALK mutation treated with alectinib is overcome by ceritinib. In this way, sequential therapy ensures the continuity of treatment. In patients with CNS metastases, attempts are made to simultaneously administer radiation therapy and tyrosine kinase inhibitors. Patients with lung adenocarcinoma with CNS metastases, without activating EGFR mutation and without ALK rearrangement, benefit from immunotherapy. This therapeutic option blocks the PD-1 receptor on the surface of T or B lymphocytes or PD-L1 located on cancer cells with an applicable antibody. Based on clinical trials, pembrolizumab and all antibodies are included in the treatment of non-small cell lung carcinoma with CNS metastases.
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Kawamura, Takahisa, Haruyasu Murakami, Haruki Kobayashi, Kazuhisa Nakashima, Shota Omori, Kazushige Wakuda, Akira Ono, et al. "Leptomeningeal recurrence after long-term alectinib therapy for non-small cell lung cancer harboring an EML4-ALK fusion protein." Investigational New Drugs 37, no. 1 (July 3, 2018): 184–87. http://dx.doi.org/10.1007/s10637-018-0633-6.
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Chen, Nan, and Robert C. Doebele. "Abstract 1100: miR205 mediates acquired resistance to ALK inhibition via targeting Mig6 expression and enhancing EGFR signaling." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1100. http://dx.doi.org/10.1158/1538-7445.am2022-1100.
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Abstract Complete responses to ALK tyrosine kinase inhibitors (TKIs) are rare and resistance eventually develops in ALK fusion-positive non-small cell lung cancer patients. To overcome resistance and improve therapeutic outcomes, it is crucial to understand the molecular mechanisms contributing to resistance. Our lab has previously shown EGFR signaling mediates adaptive resistance to ALK inhibitors. We demonstrated that RNA and protein levels of Mig6, an endogenous protein inhibitor of EGFR, were suppressed rapidly following ALK inhibition, thus unlocking EGFR from inhibition to support cell survival. In this study, we asked whether EGFR signaling activation and Mig6 suppression persist once acquired resistance is established. An EML4-ALK cell line, H3122, was continuously exposed to a fixed dose of the ALK inhibitor crizotinib to generate three resistant lines (H3122-CR1, -2, and -3). All H3122-CR lines lacked ALK kinase mutations and were also cross-resistant to other ALK TKIs including ceritinib and alectinib. We found phosphorylation and total EGFR were upregulated while Mig6 protein was attenuated across all resistant lines compared to their parental counterpart. Afatinib, a pan-ERBB family inhibitor, or Mig6 overexpression, was able to re-sensitize those resistant cells to ALK inhibition. Interestingly, we did not find Mig6 overexpression altered phosphorylation of EGFR. Previously reported data suggest that Mig6 competes with Shc1, a critical signaling adapter shared by ALK and EGFR, for the same substrate-binding cleft on EGFR. We then hypothesized Mig6 could block EGFR-Shc1 binding and downstream signaling transduction without directly impacting EGFR phosphorylation. Indeed, the co-immunoprecipitation assay showed Mig6 knockdown in H3122 cells enhanced Shc1 binding to EGFR without altering phosphorylation of EGFR itself, suggesting a novel mechanism in regulating EGFR signaling by impairing the signaling adapter binding. We then investigated the mechanism responsible for Mig6 protein attenuation in resistant lines. By examining the RNA-seq data for all the CR lines compared to the parental H3122, we found MIR205HG was substantially upregulated in resistant cells. MIR205HG is the host gene for miR-205, which was known to target ERRFI1 gene that encodes Mig6. Stem-loop RT-qPCR confirmed that miR-205 was increased ~5 fold in all CR lines. Overexpressing miR-205 in H3122 cells could downregulate Mig6 expression in a dose-dependent manner. Herein we presented a novel resistance mechanism to ALK inhibition by which miR205 upregulation attenuates Mig6 expression, releasing EGFR-Shc1 signaling transduction from inhibition to support cell survival. This study also provides additional support for targeting EGFR signaling to overcome ALK TKI resistance to improve patient survival. Citation Format: Nan Chen, Robert C. Doebele. miR205 mediates acquired resistance to ALK inhibition via targeting Mig6 expression and enhancing EGFR signaling [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 1100.
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Khthir, Rodhan, Zainab Shaheen, Prasanna Santhanam, and Saroj Sigdel. "Aggressive Differentiated Thyroid Cancer due to EML4e13-ALKe20 Fusion: A Case Presentation and Review of the Literature." Case Reports in Endocrinology 2021 (February 15, 2021): 1–7. http://dx.doi.org/10.1155/2021/8837399.
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Background. Differentiated thyroid cancer (DTC) is an indolent malignancy. It rarely presents with aggressive local invasion and/or distant metastatic disease. Patient findings. We describe a case of a 30-year-old man with a locally aggressive form of papillary thyroid cancer with EML4e13-ALKe20 fusion (EML4: echinoderm microtubule-associated protein-like 4; ALK: anaplastic lymphoma kinase). He presented with right-side cervical lymphadenopathy with a highly suspicious right-side thyroid nodule. Total thyroidectomy and level IV lymph node resection showed extensive bilateral disease, with extrathyroidal and extranodal extension. FDG-PET CT scan following surgery confirmed the presence of significant residual disease in the neck area. He underwent bilateral lateral lymph node dissection followed by radioactive iodine treatment. Somatic mutation testing showed EML4e13-ALKe20 fusion. Summary. This case represents an aggressive form of DTC with EML4e13-ALKe20 fusion. The rapid progression of clinical signs and symptoms and the local extension beyond the thyroid and lymph nodes with the persistence of high-volume local disease after thyroidectomy highlight the aggressive nature of this mutation and the importance of performing genetic analysis to guide future treatments and determine prognosis. Conclusion. This case highlights the importance of using molecular diagnostics in patient care, especially if the presentation is unusual for DTC. A thorough evaluation of the tumor pathology and the somatic mutational profile analysis are important for obtaining vital therapeutic and prognostic guidance.
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Okimoto, Tamio, Yukari Tsubata, Takamasa Hotta, Megumi Hamaguchi, Takae Okuno, Yohei Shiratsuki, Akari Kodama, et al. "Successful rechallenge with ceritinib after leukocytoclastic vasculitis during ceritinib treatment for non-small cell lung cancer harboring the EML4-ALK fusion protein." Oncotarget 9, no. 28 (April 13, 2018): 20213–18. http://dx.doi.org/10.18632/oncotarget.24765.
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Ramshankar, Vijayalakshmi, Subha Yegnaswamy, Kumarasamy P, and Krishnamurthy Arvind. "Molecular docking studies shows tivozanib and lapatinib as potential inhibitors of EML4-ALK translocation mediated fusion protein in non small cell lung cancer." Bioinformation 10, no. 10 (October 30, 2014): 658–63. http://dx.doi.org/10.6026/97320630010658.
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Hong, Shaodong, Nan Chen, Wenfeng Fang, Jianhua Zhan, Qing Liu, Shiyang Kang, Xiaobo He, et al. "Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients." OncoImmunology 5, no. 3 (December 21, 2015): e1094598. http://dx.doi.org/10.1080/2162402x.2015.1094598.
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Tyler, Logan C., Nan Chen, Anh T. Le, Hala Nijmeh, Liming Bao, and Robert C. Doebele. "Abstract 1102: Fyn and Src cooperate with ERBB family to drive resistance to crizotinib in ROS1+ and ALK+ NSCLC." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1102. http://dx.doi.org/10.1158/1538-7445.am2022-1102.
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Abstract ALK/ROS1 TKIs have significantly improved outcomes for patients with ALK/ROS1+ lung adenocarcinoma. However, drug resistance inevitably develops, leading to disease progression. Approximately 1/3 of patients resistant to ROS1 TKIs demonstrate on-target ROS1 kinase domain (KD) mutations (Dziadziuszko et al. ESMO 2019), but the mechanism of resistance in most patients remains unknown/poorly characterized. To model and characterize acquired resistance to crizotinib, we used ROS1+ and ALK+ primary, patient tumor-derived non-small cell lung cancer (NSCLC) cell lines to generate acquired resistance models to the ALK/ROS1 inhibitor crizotinib. We used several techniques to probe the mechanisms driving resistance: DNA and RNA sequencing (seq), fluorescence in-situ hybridization (FISH), cell proliferation assays, and western blotting. The crizotinib-resistant line initially driven by a TPM3-ROS1 fusion (CUTO28-CR) displayed exquisite sensitivity to Src family kinase (SFK) TKIs in proliferation assays, which was modestly improved by addition of ERBB TKI afatinib. Bulk RNA seq revealed upregulation of SFKs Fyn and Src transcripts (141- and 2.31-fold, respectively). Interphase FISH revealed modest EGFR gene amplification in CUTO28-CR cells vs parental (EGFR:CEP7 ratio 2.1 vs 1.0), and RNA seq revealed upregulation of EGFR and HER2 transcripts (1.79- and 2.45-fold, respectively). Western blot analysis confirmed upregulation of Fyn at the protein level. CUTO28-CR cells treated with a SFK TKI revealed dose-dependent deactivation of Akt signaling, and addition of afatinib caused inhibition of MAPK signaling. Stimulation with epidermal growth factor (EGF) enhanced MAPK signaling in CUTO28-CR cells more than in parental cells, consistent with EGFR/HER2 dependence. Because of a noted propensity for the EML4-ALK line (H3122) to upregulate ERBB kinase activity under sustained ALK TKI treatment, we maintained these cells in low dose (25nM) afatinib while driving crizotinib resistance to identify additional bypass signaling pathways. These H3122-CAR cells were partially resensitized to crizotinib with the addition of SFK TKIs, and the addition of afatinib with SFK TKIs further resensitized these resistant cells to crizotinib. Bulk RNA seq of H3122-CAR cells revealed upregulation of Fyn and Src (2.64- and 3.63-fold, respectively), and western blot analysis confirmed upregulation at the protein level. In conclusion, we demonstrated increased SFK (particularly Fyn and/or Src) expression and/or activation is a mechanism utilized to drive bypass signaling, in cooperation with ERBB family kinases, to circumvent treatment with ALK/ROS1 TKI crizotinib. To our knowledge, this is the first report of SFK-driven bypass signaling as a mechanism of acquired resistance to an ALK/ROS1 TKI in NSCLC. The upregulation of Src and/or Fyn in NSCLC biopsies may guide the exploration of combination SFK TKIs with ALK/ROS1 TKIs. Citation Format: Logan C. Tyler, Nan Chen, Anh T. Le, Hala Nijmeh, Liming Bao, Robert C. Doebele. Fyn and Src cooperate with ERBB family to drive resistance to crizotinib in ROS1+ and ALK+ NSCLC [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 1102.
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Farhood, Rawaa Ghalib, Kaswer Al-tariahi, Rehab Hameed Adul-Sahieb, and Afraa Mamoori. "Detection of EML4-ALK Fusion Gene Rearrangement in Non-Small Cell Lung Carcinoma in a Sample of Iraqi Patients: A Comparison of Chromogenic in Situ Hybridization with Correlation of ALK Protein Expression." Indian Journal of Public Health Research & Development 10, no. 5 (2019): 1267. http://dx.doi.org/10.5958/0976-5506.2019.01170.7.
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Yang, Xiaojuan, Diyuan Qin, Yu Zhang, Xue Li, Ning Liu, Ying Zhou, Ming Feng, and Yongsheng Wang. "An elderly female patient with ROS1 rearrangement primary lung adenocarcinoma and breast carcinoma: a rare case report and review of the literature." Precision Clinical Medicine 2, no. 3 (August 28, 2019): 197–203. http://dx.doi.org/10.1093/pcmedi/pbz013.
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Abstract We report the case of a 90-year-old female patient who was suffering from c-ros oncogene 1 (ros-1) rearrangement adenocarcinoma and breast cancer. After about 14 months of a reduced dose of crizotinib treatment, she had a stable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). This patient’s case demonstrates that ros-1 rearrangements are not limited to patients of young age. In addition, this case indicates that crizotinib, as second-line, or even first-line, treatment may be effective and manageable in elderly patients. Furthermore, for elderly patients carrying a ros1 fusion, a reduced dose of crizotinib may be efficacious rather than a resistance factor. Based on our findings, we recommend that elderly patients with advanced lung adenocarcinoma should be considered for inclusion in molecular screening for ros-1 translocation, especially for never-smokers negative for epidermal growth factor receptor (egfr) mutation and the fusion between echinoderm microtubule associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK). This deserves attention because the population is aging, with increasing incidence and morbidity of multiple primary malignant tumors. Neglect of breast nodules at the onset is one of the limitations of our case, as combination of primary lung cancer with breast cancer is common. Above all, use of antiestrogens before and after the diagnosis of non-small-cell lung cancer is related to a reduced risk of lung cancer mortality. Therefore, careful attention should always be paid to these cases.
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Kumar, Pragya, Virginia Turati, and Andriy Marusyk. "Abstract B032: Deciphering the mechanisms of environmentally mediated Alectinib resistance in ALK+NSCLC." Cancer Research 82, no. 10_Supplement (May 15, 2022): B032. http://dx.doi.org/10.1158/1538-7445.evodyn22-b032.
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Abstract Non-small cell lung cancer (NSCLC) is a devastating disease with a subset containing targetable oncogenic mutations that strongly benefit from targeted therapies. 3-7% of NSCLC patients bear an amplification of the Anaplastic lymphoma kinase (ALK) and Echinoderm microtubule-associated protein like 4 (EML4) fusion gene. These tumors typically show strong durable responses to first line therapy, Alectinib, an ALK tyrosine kinase inhibitors (ALK-TKIs). However, there is a high degree of patient-to-patient variability in the level of response to this drug; with some patients being innately resistant or less sensitive. Moreover, weak initial sensitivity to therapy has been linked to poor long-term responses with early acquisition of resistance. Thus, to improve clinical outcomes, we need to understand the mechanisms that lead to this reduced sensitivity to ALK inhibition. While, historically, reduced sensitivity to ALK TKI was thought to reflect cell intrinsic mechanisms, a growing body of evidence points to the importance of tumor microenvironmentally (TME) mediated mechanisms. We fortuitously encountered an observation of strong environment-mediated desensitization to Alectinib. We found that combining Alectinib with a small molecule inhibitor, Jumonji histone demethylase inhibitor, JIB04 in vitro overcomes tolerance, preventing ALK+NSCLC cells from developing resistance to Alectinib. Surprisingly, our validation experiments in mouse models revealed the opposite effect, where, JIB04 desensitized tumors to ALK inhibition. The disparity in the in vitro versus the in vivo response indicates the contribution of the TME in the reduced Alectinib sensitivity observed in vivo. The resistance phenotype in Alectinib+JIB04 treated mice was strongly associated with extensive inflammation in the tumor proximal tissues, along with higher circulating levels of inflammatory markers, IL6, LIF and monocytes, suggesting that inflammation may play a role in mediating this resistance. This is consistent with the recent findings where the markers of systemic inflammation such as Neutrophil to Lymphocyte ratio (NLR) have been associated with poor prognosis in ALK+NSCLC. While the mechanistic understanding is not well characterized, our model may help us explore the mechanisms of this correlation. Thus, our objective is to understand the underlying microenvironmental mechanism of this resistance to Alectinib. We hypothesize that Alectinib+JIB04 associated inflammation reduces ALK+NSCLC’s sensitivity to Alectinib. We envision two possibilities, either inflammation may directly affect resistance to Alectinib or indirectly where inflammation enhances tumor cell plasticity that then leads to resistance. We posit that the underlying molecular mechanisms of Alectinib+JIB04 mediated resistance are likely to be relevant to a subset of patients with poor initial responses with weak sensitivity or innate resistance to Alectinib observed in the clinics and will improve our knowledge about microenvironmental regulation of resistance. Citation Format: Pragya Kumar, Virginia Turati, Andriy Marusyk. Deciphering the mechanisms of environmentally mediated Alectinib resistance in ALK+NSCLC [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B032.
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Foltz, Steven M., Qingsong Gao, Christopher J. Yoon, Amila Weerasinghe, Hua Sun, Lijun Yao, Mark A. Fiala, et al. "Comprehensive Multi-Omics Analysis of Gene Fusions in a Large Multiple Myeloma Cohort." Blood 132, Supplement 1 (November 29, 2018): 1898. http://dx.doi.org/10.1182/blood-2018-99-117245.
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Abstract Introduction: Gene fusions are the result of genomic rearrangements that create hybrid protein products or bring the regulatory elements of one gene into close proximity of another. Fusions often dysregulate gene function or expression through oncogene overexpression or tumor suppressor underexpression (Gao, Liang, Foltz, et al. Cell Rep 2018). Some fusions such as EML4--ALK in lung adenocarcinoma are known druggable targets. Fusion detection algorithms utilize discordantly mapped RNA-seq reads. Careful consideration of detection and filtering procedures is vital for large-scale fusion detection because current methods are prone to reporting false positives and show poor concordance. Multiple myeloma (MM) is a blood cancer in which rapidly expanding clones of plasma cells spread in the bone marrow. Translocations that juxtapose the highly-expressed IGH enhancer with potential oncogenes are associated with overexpression of partner genes, although they may not lead to a detectable gene fusion in RNA-seq data. Previous studies have explored the fusion landscape of multiple myeloma cohorts (Cleynen, et al. Nat Comm 2017; Nasser, et al. Blood 2017). In this study, we developed a novel gene fusion detection pipeline and post-processing strategy to analyze 742 patient samples at the primary time point and 64 samples at follow-up time points (806 total samples) from the Multiple Myeloma Research Foundation (MMRF) CoMMpass Study using RNA-seq, WGS, and clinical data. Methods and Results: We overlapped five fusion detection algorithms (EricScript, FusionCatcher, INTEGRATE, PRADA, and STAR-Fusion) to report fusion events. Our filtered call set consisted of 2,817 fusions with a median of 3 fusions per sample (mean 3.8), similar to glioblastoma, breast, ovarian, and prostate cancers in TCGA. Major recurrent fusions involving immunoglobulin genes included IGH--WHSC1 (88 primary samples), IGL--BMI1 (29), and the upstream neighbor of MYC, PVT1, paired with IGH (6), IGK (3), and IGL (11). For each event, we used WGS data when available to determine if there was genomic support of the gene fusion (based on discordant WGS reads, SV event detection, and MMRF CoMMpass Seq-FISH WGS results) (Miller, et al. Blood 2016). WGS validation rates varied by the level of RNA-seq evidence supporting each fusion, with an overall rate of 24.1%, which is comparable to previously observed pan-cancer validation rates using low-pass WGS. We calculated the association between fusion status and gene expression and identified genes such as BCL2L11, CCND1/2, LTBR, and TXNDC5 that showed significant overexpression (t-test). We explored the clinical connections of fusion events through survival analysis and clinical data correlations, and by mining potentially druggable targets from our Database of Evidence for Precision Oncology (dinglab.wustl.edu/depo) (Sun, Mashl, Sengupta, et al. Bioinformatics 2018). Major examples of upregulated fusion kinases that could potentially be targeted with off-label drug use include FGFR3 and NTRK1. We examined the evolution of fusion events over multiple time points. In one MMRF patient with a t(8;14) translocation joining the IGH locus and transcription factor MAFA, we observed IGH fusions with TOP1MT (neighbor of MAFA) at all four time points with corresponding high expression of TOP1MT and MAFA. Using non-MMRF single-cell RNA data from different patients, we were able to track cell-type composition over time as well as detect subpopulations of cells harboring fusions at different time points with potential treatment implications. Discussion: Gene fusions offer potential targets for alternative MM therapies. Careful implementation of gene fusion detection algorithms and post-processing are essential in large cohort studies to reduce false positives and enrich results for clinically relevant information. Clinical fusion detection from untargeted RNA-seq remains a challenge due to poor sensitivity, specificity, and usability. By combining MMRF CoMMpass data from multiple platforms, we have produced a comprehensive fusion profile of 742 MM patients. We have shown novel gene fusion associations with gene expression and clinical data, and we identified candidates for druggability studies. Disclosures Vij: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Rossi, Elisabetta, Michele Aieta, Alfredo Tartarone, Aldo Pezzuto, Antonella Facchinetti, Daniele Santini, Paola Ulivi, et al. "A fully automated assay to detect the expression of pan-cytokeratins and of EML4-ALK fusion protein in circulating tumour cells (CTCs) predicts outcome of non-small cell lung cancer (NSCLC) patients." Translational Lung Cancer Research 10, no. 1 (January 2021): 80–92. http://dx.doi.org/10.21037/tlcr-20-855.
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Manjon, Nuria, Jaime Martinez, Gonzalo Garcia, Ana Aragon, Jaime Carrillo, Jose Luis Rodriguez-Peralto, Jose Ramón Antunez Lopez, Javier Hernandez-Losa, Rosario Cospedal, and Maria Luisa Villahermosa. "A new diagnostic method based on RT-PCR and CLART technology for non-small cell lung cancer (NSCLC) to detect major EML4-ALK and ROS.1 translocations: CLART CMA ALK and ROS.1." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20045-e20045. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20045.
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e20045 Background: EML4-ALK and ROS1 translocations represent 3-6% and 1-2% of NSCLC patients, respectively. These patients would benefit for a tyrosine kinase inhibitor therapies. Currently, the gold standard for ALK and ROS.1 detection are break-apart fluorescence in situ hybridization (FISH) or inmunodetection (IHC) of the chimeric fusion proteins. FISH has both high sensitivity and specificity, although often present technical interpretation problems due to signal instability and scoring. IHC is a rapid and low cost technique; however it presents several challenges regarding sensitivity and reproducibility. CLART CMA ALK & ROS.1 kit is based RT-PCR and detection of the amplified product was carried out by a low-density microarray platform: CLART (Clinical Arrays Technology) of major fusion transcripts of EML4-ALK and ROS.1 translocations ( V1: E13;A20 , V6: E13; ins69;A20 , V2: E20;A20 , V3a: E6:A20 , V3b: E6;ins33 A20 ,V5a: E2;A20 and V5b: E2;ins117A20 for EML4-ALK and SDC4-ROS1 S2;R32/ S2;R34, CD74-ROS1 C6;R34 and SLC34A2-ROS1 S4;R32/S4;R34). Methods: The translocations analysis was performed with CLART CMA ALK & ROS.1 kit. Clinical testing was performed using the RNA extracted from 115 samples of NSCLC patients being 34 patients with translocations detected in ALK or ROS.1 genes and 81 patients without any translocations. The results were cross-checked by comparison to Next GenerationS methodology performed on the PGM platform with the Ion Ampliseq Panel Oncomide Solid Tumor Fusion and the concordance was 95.6%. Results: Analytical sensitivity was assessed using fusion transcripts cloned in recombinant plasmids. Results ranged from 10 to 100 copies/5µl of recombinant plasmids. The analysis of 115 clinical samples allowed establishing the diagnostic sensitivity and specificity in 90.9-100% and 99-100% respectively. Conclusions: CLART CMA ALK & ROS.1 emerges as a suitable alternative of FISH/IHQ for diagnosis of the most common translocations in EML4-ALK and ROS.1 genes in NSCLC samples and therefore selecting patients that would best benefit from a target therapy.
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Li, Bin, Yongbin Hu, Qiongzhi He, Jingchen Lu, Gengwen Huang, and Sheng Xiao. "Loss of 5'ALK leads to better response to crizotinib in sarcomas with ALK rearrangement." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e23554-e23554. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e23554.
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e23554 Background: Crizotinib targets abnormal ALK activation, however, the clinical responses vary among patients with ALK rearrangement. A recent study showed that the NSCLC patients with 5'ALK loss have a favorable response to Crizotinib with doubled progression-free survival (PFS). We asked whether sarcoma patients with ALK rearrangement have a similar correlation between 5'ALK loss and clinical response to Crizotinib. Methods: The histopathologic diagnosis was made on H&E staining and IHC, including anti-ALK(D5F3). DNA isolated from FFPE materials was subjected to an NGS assay targeting 295 genes including ALK rearrangement. Results: 4 cases were detailed in Table. Case#1 is an inflammatory myofibroblastic tumor with a PLEKHH2-ALK rearrangement, which was previously reported in an NSCLC but not in sarcomas. Case #2 is an undifferentiated sarcoma with 2 ALK fusions, RANBP2-ALK and TMEM217-ALK, both in-frame fusions containing intact tyrosine kinase domains. The TMEM217-ALK is a novel fusion. Case#3 is a leiomyosarcoma with MYH9-ALK fusion, which was often seen in ALK-positive large B-cell lymphoma but not in sarcoma. Case #4 is an undifferentiated sarcoma with EML4-ALK fusion. All 4 cases had positive ALK IHC, consistent with the expression of ALK fusion proteins. Case#1 and #2 had a loss of 5' ALK, while case #3 and #4 retained the 5' ALK. All cases received and responded to Crizotinib therapy, with the Karnofsky Performance Status (KPS) improved from 30-60 score pre-therapy to 90-100 score after 3 months of Crizotinib. While Case#3 and #4, both retained the 5' ALK, relapsed at 9.4 m and 6.1 m, case#1 and #2, both lost 5' ALK, remain progression-free at 15m and 27m, respectively. The side effect was manageable with a grade II hepatic toxicity in only one patient. Conclusions: We report here 4 sarcomas with ALK rearrangement, including a novel fusion TMEM217-ALK. Two of these cases had a 5' ALK loss in addition to the 3' ALK rearrangement, and both had much longer PFS on Crizotinib therapy. The underlying mechanism deserved further investigation. Four fibrosarcomas with ALK rearrangements and their response to Crizotinib therapy.[Table: see text]
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Smolle, Elisabeth, Valentin Taucher, Joerg Lindenmann, Philipp J. Jost, and Martin Pichler. "Current Knowledge about Mechanisms of Drug Resistance against ALK Inhibitors in Non-Small Cell Lung Cancer." Cancers 13, no. 4 (February 9, 2021): 699. http://dx.doi.org/10.3390/cancers13040699.
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Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer subtypes. Two to seven percent of NSCLC patients harbor gene rearrangements of the anaplastic lymphoma kinase (ALK) gene or, alternatively, harbor chromosomal fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4). The availability of tyrosine kinase inhibitors targeting ALK (ALK-TKIs) has significantly improved the progression-free and overall survival of NSCLC patients carrying the respective genetic aberrations. Yet, increasing evidence shows that primary or secondary resistance to ALK-inhibitors during the course of treatment represents a relevant clinical problem. This necessitates a switch to second- or third-generation ALK-TKIs and a close observation of NSCLC patients on ALK-TKIs during the course of treatment by repetitive molecular testing. With this review of the literature, we aim at providing an overview of current knowledge about resistance mechanisms to ALK-TKIs in NSCLC.
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Watanabe, Satoshi, Kazuko Sakai, Naoya Matsumoto, Jun Koshio, Akira Ishida, Tetsuya Abe, Daisuke Ishikawa, et al. "Phase II Trial of the Combination of Alectinib with Bevacizumab in Alectinib Refractory ALK-Positive Nonsquamous Non-Small-Cell Lung Cancer (NLCTG1501)." Cancers 15, no. 1 (December 29, 2022): 204. http://dx.doi.org/10.3390/cancers15010204.
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Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2–16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.
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Proia, David A., Jaime Acquaviva, Qin Jiang, Liquan Xue, Donald Smith, Julie C. Friedland, Suqin He, Jim Sang, Stephan Morris, and Yumiko Wada. "Preclinical activity of the Hsp90 inhibitor, ganetespib, in ALK- and ROS1-driven cancers." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 3090. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3090.
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3090 Background: Ganetespib is a potent inhibitor of heat shock protein 90 (Hsp90) currently being studied in a broad range of clinical trials. Phase II results with ganetespib demonstrated an encouraging objective response rate of 50% in non-small cell lung carcinoma (NSCLC) patients whose tumors contained ALK translocations and had progressed on previous treatments. To further understand the clinical potential of ganetespib in ALK-driven cancers, we evaluated its activity in (1) crizotinib-sensitive and -resistant cancer cells harboring ALK fusions; (2) cells expressing amplified ALK or ROS1 translocations (a kinase structurally similar to ALK); and (3) in combination with crizotinib. Methods: H3122 NSCLC cells, which express EML4-ALK, were treated with ganetespib, crizotinib or the combination, and cell viability and signaling cascades were assessed. Similar experiments were done in cells with amplified, constitutively active ALK (NB-39-nu) or ROS1 kinase fusions (HCC-78, U118MG). To generate a model of crizotinib resistance, NPM-ALK-expressing BaF3 cells were exposed to various crizotinib concentrations. Fifteen different ALK kinase domain substitutions were identified; clonal NPM-ALK/BaF3 cells were made for each resistance mutation and assayed for sensitivity to ganetespib. Results: Ganetespib was 50-fold more potent than crizotinib in killing H3122 cells, and when combined together at sub-lethal doses, displayed strong synergistic anticancer activity. Ganetespib showed similar potency in other cells driven by constitutively active ALK or ROS1 kinase fusions, due to abrogation of their oncogenic kinase activity. All 15 of the crizotinib-resistant NPM-ALK/BaF3 mutant clones were highly sensitive to ganetespib (IC50 values ranging from 14-23 nM), including the 7 mutations reported to date in patients with ALK-driven tumors. Conclusions: Ganetespib effectively inhibits the activity of ALK and ROS1, kinases associated with several tumor types, resulting in marked single agent anticancer activity in cells driven by them. Importantly, ganetespib retains its potency irrespective of the mutational status of ALK. The strong synergy observed between ganetespib and crizotinib warrants further study.
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Li, Yongjun, Xiaofen Ye, Jinfeng Liu, Jiping Zha, and Lin Pei. "Evaluation of EML4-ALK Fusion Proteins in Non–Small Cell Lung Cancer Using Small Molecule Inhibitors." Neoplasia 13, no. 1 (January 2011): 1—IN1. http://dx.doi.org/10.1593/neo.101120.
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O'Regan, Laura, Giancarlo Barone, Rozita Adib, Chang Gok Woo, Hui Jeong Jeong, Emily L. Richardson, Mark W. Richards, et al. "EML4–ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7." Journal of Cell Science 133, no. 9 (March 17, 2020): jcs241505. http://dx.doi.org/10.1242/jcs.241505.
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Xu, Chunwei, Wen-xian Wang, Meiyu Fang, Yan-ping Chen, Yu Chen, Li-hua Zhong, Fang-fang Chen, et al. "Parallel VENTANA IHC and RT-PCR of ALK status in non-small cell lung cancer and response to crizotinib." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11623. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11623.
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11623 Background: Advanced NSCLC patients who harbor (ALK) rearrangement were sensitive to crizotinib. However, not all ALK-positive patients benefit equally from crizotinib. A method for determining ALK rearrangement is RT-PCR, the Chinese FDA has approved RT-PCR to detect ALK rearrangement. In this regard, VENTANA IHC is a standard method to identify ALK protein overexpression in NSCLC. However, up to now, it is still largely unknown about the response to crizotinib for Chinese NSCLC patients having ALK overexpress detected by VENTANA IHC. To better clarify the clinical implication of VENTANA IHC to detect ALK rearrangement, we compared the curative effect and survival by the two methods in advanced NSCLC patients and analysis VENTNA IHC and RT-PCR inconsistent cases. Methods: A total of 1720 patients with NSCLC who had their ALK rearrangement detected by IHC and/or RT-PCR were included in this analysis. And we compared the efficacy and survival of patients with ALK positive detected by IHC and RT-PCR. We used next-generation sequencing (NGS) to detect patients whom two methods were not consistent. Results: 187/1720 patients were identified as ALK-positive by IHC and/or RT-PCR and 66 patient received crizotinib. We identified 172/1674 patients had ALK positive by IHC method, 41/322 patients had ALK rearrangements by RT-PCR method. And 29/276 patients with ALK positive were simultaneously analyzed by IHC and RT-PCR. The overall response rates (ORR) were 65.90% by IHC and 55.88% by RT-PCR, respectively. And the disease control rates (DCR) were 86.36% by IHC and 76.47% by RT-PCR. The median PFS of IHC was 8.5 months and RT-PCR was 9.2 months Targeted next-generation sequencing in the special type: Among 6 cases of 17 cases ALK positive patients were inconsistent by IHC and RT-PCR performed with NGS, 4 cases were identified to have EML4-ALK fusions, and 2 cases were KCL1-ALK(ND) and FBXO36-ALK (PFS 21.2 months). Conclusions: VENTANA IHC is a reliable and rapid screening tool in routine pathologic laboratories for the identification of suitable candidates for targeted therapy. It has a moderate sensitivity and a slightly higher curative effect, and some VENTANA IHC positive but RT-PCR negative cases may benefit from crizotinib.