Sensitivity to EGFR inhibitors based on location of EGFR exon 20 insertion mutations within the tyrosine kinase domain of EGFR.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7523-7523 ◽  
Author(s):  
Daniel Botelho Costa ◽  
Hiroyuki Yasuda ◽  
Natasha J Sng ◽  
Wee-Lee Yeo ◽  
Lorena Lobo de Figueiredo-Pontes ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Line ◽  
Molecular Mechanisms ◽  
Site Directed Mutagenesis ◽  
Egfr Mutations ◽  
Tyrosine Kinase Domain ◽  
Exon 20 ◽  
Insertion Mutations ◽  
Egfr Tkis

7523 Background: Epidermal growth factor receptor (EGFR) mutations (M) define an important subgroup of non-small-cell lung cancer (NSCLC). Most patients whose tumors harbor exon 19 deletions or L858R EGFR M have responses to reversible ATP-mimetic EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. Exon 20 insertion M comprise ~5% of EGFR M, occur at the N-lobe of EGFR after its C-helix (AA M766), and nearly all NSCLCs with EGFR exon 20 insertion M display lack of responses to EGFR TKIs (Yasuda H. Lancet Oncol 2011). Methods: We have 1) compiled genotype-clinical outcomes of EGFR exon 20 insertion M NSCLCs to EGFR TKIs, 2) generated a comprehensive panel of exon 20 EGFR M constructs using site-directed mutagenesis and introduced them into Ba/F3 cells for in vitro analysis, and 3) compared NSCLC cell lines with EGFR M to a novel malignant pleural effusion-derived cell line. Results: The disease control rate of gefitinib or erlotinib was significantly higher in EGFR exon 20 insertion M located within the C-helix (3/3,100%) when compared to M following the C-helix (1/14, 7%; p=0.00059). The NSCLC with EGFR-A763_Y764insFQEA (located within the C-helix of EGFR) achieved a partial response to erlotinib that lasted 18 months. Most other exon 20 insertion M-positive NSCLCs did not respond (p=0.07). Eight representative exon 20 insertion M were studied (including EGFR-A763_Y764insFQEA, Y764_S765insHH, A767_V769dupASV, D770_N771insNPG, H773_V774insH). All, but A763_Y764insFQEA, were resistant to micromolar concentrations (C) of EGFR TKIs. Ba/F3 cells with EGFR-A763_Y764insFQEA underwent apoptosis upon exposure to nanomolar C of erlotinib. A patient-derived cell line with EGFR-A763_Y764insFQEA had phosphorylated EGFR, ERK and AKT inhibited by nanomolar C of erlotinib. Conclusions: Not all EGFR exon 20 insertion mutations are resistant to EGFR TKIs, and in specific EGFR-A763_Y764insFQEA is an EGFR TKI-sensitive M. This finding has clinical implications for the care of the 10,000 cases of EGFR exon 20 insertion M NSCLC diagnosed yearly and points towards the need to define the molecular mechanisms that underlie differential responses to EGFR TKIs.

Transforming and Tumorogenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosin-Kinase.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4683-4683
Author(s):  
Álvaro Cuesta-Domínguez ◽  
Mara Ortega ◽  
Cristina Ormazabal ◽  
Matilde Santos-Roncero ◽  
Marta Galán-Díez ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Nude Mice ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Chimeric Protein ◽  
Tyrosine Kinase Domain ◽  
Molecular Response

Abstract Abstract 4683 Chromosomal translocations in human tumors frequently produce fusion genes whose chimeric protein products play an essential role in oncogenesis. Recent reports have found a BCR-JAK2 fusion gene in cases of chronic or acute myeloid leukemia, but the protein had not been characterized. We describe a BCR-JAK2 fusion gene by fluorescence in situ hybridization and RT-PCR amplification from bone marrow at diagnosis of a patient with acute lymphoblastic leukemia. After induction therapy, real time PCR showed persistent molecular response correlating with hematological remission maintained up to present. BCR-JAK2 is a 110 KDa chimeric protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis showed that BCR-JAK2 was constitutively phosphorylated and was located to the cytoplasm. BCR-JAK2 transformed the IL-3-dependent murine hematopoietic cell line Ba/F3 into IL-3 independent growth and induced STAT5b phosphorylation and translocation into the cell nuclei. The treatment with a JAK2 inhibitor abrogated BCR-JAK2 and STAT5b phosphorylation, leading to apoptosis of transformed Ba/F3 cells. To test whether BCR-JAK2 has tumorogenic ability in vivo, we performed experiments with nude mice, in which we injected subcutaneously cells transduced with the control vector and cells expressing BCR-JAK2. Notably, we only obtained tumors in the flank injected with BCR-JAK2 expressing cells, thus confirming the tumorogenic activity of the BCR-JAK2 fusion protein. We conclude that BCR-JAK2 is a new tyrosine-kinase that induces proliferation and cell survival, which can be abrogated by JAK2 inhibitors. In vitro studies demonstrate that BCR-JAK2 displays transforming activity. Moreover, the nude mice model reveals its ability to cause tumors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Novel Activating Mutation in the RET Tyrosine Kinase Domain Mediates Neoplastic Transformation

2006 ◽  
Vol 20 (7) ◽  
pp. 1633-1643 ◽  
Author(s):  
Aaron Cranston ◽  
Cristiana Carniti ◽  
Sam Martin ◽  
Piera Mondellini ◽  
Yvette Hooks ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Functional Characterization ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Exogenous Substrate

Abstract We report the finding of a novel missense mutation at codon 833 in the tyrosine kinase of the RET proto-oncogene in a patient with a carcinoma of the thyroid. In vitro experiments demonstrate that the R833C mutation induces transformed foci only when present in the long 3′ splice isoform and, in keeping with a model in which the receptor has to dimerize to be completely activated, glial cell line-derived neurotrophic factor stimulation leads the RETR833C receptor to a higher level of activation. Tyrosine kinase assays show that the RETR833C long isoform has weak intrinsic kinase activity and phosphorylation of an exogenous substrate is not elevated even in the presence of glial cell line-derived neurotrophic factor. Furthermore, the R833C mutation is capable of sustaining the transformed phenotype in vivo but does not confer upon the transformed cells the ability to degrade the basement membrane in a manner analogous to metastasis. Our functional characterization of the R833C substitution suggests that, like the V804M and S891A mutations, this tyrosine kinase mutation confers a weak activating potential upon RET. This is the first report demonstrating that the introduction of an intracellular cysteine can activate RET. However, this does not occur via dimerization in a manner analogous to the extracellular cysteine mutants.

scholarly journals The SLC34A2-ROS-HIF-1-induced up-regulation of EZH2 expression promotes proliferation and chemo-resistance to apoptosis in colorectal cancer

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Xu Li ◽  
Junjie Xing ◽  
Hantao Wang ◽  
Enda Yu
Keyword(s):  
Colorectal Cancer ◽  
Cell Line ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Site Directed Mutagenesis ◽  
Epithelial Cell Line ◽  
Ros Generation ◽  
Ezh2 Expression

AbstractGrowing evidence has uncovered that SLC34A2 plays an evident role in the progression in several types of tumors. However, the biological function and underlying molecular mechanisms of SLC34A2 remain largely unknown. Here, we indicated that SLC34A2 expression was markedly increased in SW480 and HT29 cell line cells compared with that in normal colorectal epithelial cell line cells. Array analysis displayed that the expression of enhancer of zeste 2 (EZH2) decreased considerably when SLC34A2 was knocked down. We demonstrated that SLC34A2 induced EZH2 expression and activated its promoter activity. Serial 5′ deletion and site-directed mutagenesis revealed that the induction of EZH2 expression by SLC34A2 was dependent upon the hypoxia-inducible factor 1 (HIF-1)-2 binding site directly within EZH2 promoter. Moreover, HIF-1 activation was proved essential for SLC34A2-induced EZH2 expression. Reactive oxygen species (ROS) generation contributed to the stabilization of HIF-1α by leading to the binding of HIF-1α to the EZH2 promoter, which resulted in increased EZH2 expression. Additionally, we showed that the inhibition of both HIF-1α expression and ROS generation by YC-1 or BHA, respectively, decreased SLC34A2-induced EZH2 overexpression. Significantly, SLC34A2-induced EZH2 overexpression promoted the proliferation and chemo-resistance to apoptosis in colorectal cancer (CRC) cells in vitro and in vivo. Altogether, we conclude that the SLC34A2-ROS-HIF-1-induced overexpression of EZH2 promotes CRC cells proliferation and chemo-resistance to apoptosis. SLC34A2-ROS-HIF-1-EZH2 signaling pathway might serve as a novel therapeutic target against CRC.

The spectrum of activating EGFR mutations from cell-free DNA (cfDNA) in large pancreatic cancer cohort.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 237-237
Author(s):  
Kristin Sedgwick Price ◽  
Lesli Ann Kiedrowski ◽  
Fernando I. De Zarraga ◽  
Mike Cusnir ◽  
Richard B. Lanman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Median Number ◽  
Kinase Domain ◽  
Egfr Mutations ◽  
Tyrosine Kinase Domain ◽  
Rapid Progression ◽  
Activating Mutations ◽  
Domain 3 ◽  
Exon 20 ◽  
Egfr Tkis

237 Background: Metastatic pancreatic cancer (mPC) is one of the deadliest cancers with a < 10% 5-year survival rate. Poor prognosis is well established with lack of response to or rapid progression on existing chemotherapy options. Targeted therapies, like EGFR-TKIs, have been shown to increase survival in other solid tumors like NSCLC with certain oncogenic drivers. Although treatment with the EGFR-TKI erlotinib, in combination with gemcitabine, is available for patients (pts) with mPC, the survival benefit is small in unselected patients. A better understanding of the spectrum of EGFR mutations in mPC may lead to improved therapy selection. Methods: We retrospectively reviewed genomic results from 2,938 consecutive mPC pt samples sent for ctDNA NGS analysis between 7/2014 - 9/2018 (Guardant Health, Inc.). All reported EGFR mutations were reviewed and activating mutations were determined based on literature review. Results: 19 EGFR activating mutations were identified in 16 unique pts (0.66% of total mPC pts with alterations detected). 3 mutations were identified in the extracellular domain and 16 mutations in the tyrosine kinase domain (3 in exon 18, 3 in exon 19, 6 in exon 20, 4 in exon 21). Alterations in exon 20 included 5 T790M mutations; two of these were reported at allelic frequencies suggestive of germline origin. Analysis of co-mutations revealed 7 pts with EGFR mutations that appeared subclonal relative to other potential drivers (4 KRAS, 2 ERBB2, 1 GNAS). The median number of alterations per sample was 4 (range 2-170) with the latter pt exhibiting a hypermutator phenotype. Multiple pts had more than one activating EGFR alteration including one who was found to have 4 EGFR sequence alterations (S768I, L861Q, T790M, p.Val769_Asp770insMet) plus EGFR amplification (plasma copy number 66.8). We will collect and report clinical details to characterize the treatment context for these pts. Conclusions: Activating EGFR mutations in mPC are rare but may present an opportunity for targeted therapy in this population. Further exploration is warranted to better understand the oncogenic activity of less common, subclonal, or co-occurring EGFR mutations and their sensitivity to EGFR-TKIs in mPC.

scholarly journals EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3561
Author(s):  
Ikei S. Kobayashi ◽  
Hollis Viray ◽  
Deepa Rangachari ◽  
Susumu S. Kobayashi ◽  
Daniel B. Costa
Keyword(s):  
Clinical Care ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Insertion Mutant ◽  
Preclinical Models ◽  
2Nd Generation ◽  
Clinical Scenarios ◽  
Exon 20 ◽  
Insertion Mutations ◽  
Egfr Tkis

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving EGFR-D770 to EGFR-G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. EGFR-D770>GY and other EGFR insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of EGFR exon 20 insertion mutated lung cancer (n = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and dacomitinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with EGFR-G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at <4% of all exon 20 insertion mutations, EGFR-G770 equivalence exon 20 insertion mutations are sensitive to approved 2nd generation EGFR TKIs and EGFR exon 20 insertion mutant-active TKIs (mobocertinib and poziotinib). EGFR-D770>GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration.

scholarly journals Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations

2020 ◽  
Author(s):  
Pedro E. N. S. Vasconcelos ◽  
Ikei S. Kobayashi ◽  
Susumu S. Kobayashi ◽  
Daniel B. Costa
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Therapeutic Window ◽  
Mechanisms Of Resistance ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Exon 20 ◽  
Egfr Tki ◽  
Insertion Mutations ◽  
Egfr Tkis

AbstractBackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Novel EGFR-TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR-TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR-TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S).MethodsWe used models of EGFR mutations to probe representative 1st, 2nd, 3rd generation, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance.ResultsCells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, H773_V774insH and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to >200-fold resistance in proliferation assays probing mobocertinib and osimertinib. Review of clinical studies of mobocertinib disclosed responses that could be lasting.ConclusionsThis is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; as well as EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.

FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L)

Blood ◽  
2005 ◽  
Vol 105 (9) ◽  
pp. 3679-3685 ◽  
Author(s):  
Ksenia Bagrintseva ◽  
Stefanie Geisenhof ◽  
Ruth Kern ◽  
Sabine Eichenlaub ◽  
Carola Reindl ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Kinase Domain ◽  
Model Systems ◽  
Cytotoxic Agents ◽  
Tyrosine Kinase Domain ◽  
Vitro Model ◽  
G2m Phase

AbstractFLT3 (fms-like tyrosine kinase 3) is constitutively activated in about 30% of patients with acute myeloid leukemia (AML) and represents a disease-specific molecular marker. Although FLT3-LM (length mutation) and TKD (tyrosine kinase domain) mutations have been considered to be mutually exclusive, 1% to 2% of patients carry both mutations. However, the functional and clinical significance of this observation is unclear. We demonstrate that FLT3-ITD-TKD dual mutants induce drug resistance toward PTK inhibitors and cytotoxic agents in in vitro model systems. As molecular mechanisms of resistance, we found that FLT3-ITD-TKD mutants cause hyperactivation of STAT5 (signal transducer and activator of transcription-5), leading to upregulation of Bcl-x(L) and RAD51 and arrest in the G2M phase of the cell cycle. Overexpression of Bcl-x(L) was identified as the critical mediator of drug resistance and recapitulates the PTK inhibitor and daunorubicin-resistant phenotype in FLT3-ITD cells. The combination of rapamycin, a selective mTOR inhibitor, and FLT3 PTK inhibitors restored the drug sensitivity in FLT3 dual mutant–expressing cells. Our data provide the molecular basis for understanding clinical FLT3 PTK inhibitor resistance and point to therapeutical strategies to overcome drug resistance in patients with AML.

scholarly journals Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury

2021 ◽  
Vol 22 (2) ◽  
pp. 792
Author(s):  
Tohru Ohmori ◽  
Toshimitsu Yamaoka ◽  
Koichi Ando ◽  
Sojiro Kusumoto ◽  
Yasunari Kishino ◽  
...  
Keyword(s):  
Lung Injury ◽  
Tyrosine Kinase ◽  
Performance Status ◽  
Cytotoxic Agents ◽  
Egfr Mutations ◽  
Poor Performance Status ◽  
Chronic Obstructive ◽  
Tki Treatment ◽  
Egfr Tki ◽  
Egfr Tkis

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

scholarly journals Anti-Fibrosis Effects of Magnesium Lithospermate B in Experimental Pulmonary Fibrosis: By Inhibiting TGF-βRI/Smad Signaling

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1715
Author(s):  
Xin Luo ◽  
Qiangqiang Deng ◽  
Yaru Xue ◽  
Tianwei Zhang ◽  
Zhitao Wu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Cell Line ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Salvia Miltiorrhiza ◽  
A549 Cells ◽  
Epithelial Cell Line ◽  
Human Lung Fibroblast ◽  
Magnesium Lithospermate B

Pulmonary fibrosis is a severe and irreversible interstitial pulmonary disease with high mortality and few treatments. Magnesium lithospermate B (MLB) is a hydrosoluble component of Salvia miltiorrhiza and has been reported to have antifibrotic effects in other forms of tissue fibrosis. In this research, we studied the effects of MLB on pulmonary fibrosis and the underlying mechanisms. Our results indicated that MLB treatment (50 mg/kg) for seven days could attenuate bleomycin (BLM)-induced pulmonary fibrosis by reducing the alveolar structure disruption and collagen deposition in the C57 mouse model. MLB was also found to inhibit transforming growth factor-beta (TGF-β)-stimulated myofibroblastic transdifferentiation of human lung fibroblast cell line (MRC-5) cells and collagen production by human type II alveolar epithelial cell line (A549) cells, mainly by decreasing the expression of TGF-β receptor I (TGF-βRI) and regulating the TGF-β/Smad pathway. Further studies confirmed that the molecular mechanisms of MLB in BLM-induced pulmonary fibrosis mice were similar to those observed in vitro. In summary, our results demonstrated that MLB could alleviate experimental pulmonary fibrosis both in vivo and in vitro, suggesting that MLB has great potential for pulmonary fibrosis treatment.

scholarly journals Analysis of a Preliminary microRNA Expression Signature in a Human Telangiectatic Osteogenic Sarcoma Cancer Cell Line

2021 ◽  
Vol 22 (3) ◽  
pp. 1163
Author(s):  
Gaia Palmini ◽  
Cecilia Romagnoli ◽  
Simone Donati ◽  
Roberto Zonefrati ◽  
Gianna Galli ◽  
...  
Keyword(s):  
Cell Line ◽  
Molecular Mechanisms ◽  
Osteogenic Sarcoma ◽  
Cancer Cell Line ◽  
Microscopic Features ◽  
In Vitro Establishment ◽  
Profile Characteristic ◽  
First Time

Telangiectatic osteosarcoma (TOS) is an aggressive variant of osteosarcoma (OS) with distinctive radiographic, gross, microscopic features, and prognostic implications. Despite several studies on OS, we are still far from understanding the molecular mechanisms of TOS. In recent years, many studies have demonstrated not only that microRNAs (miRNAs) are involved in OS tumorigenesis, development, and metastasis, but also that the presence in high-grade types of OS of cancer stem cells (CSCs) plays an important role in tumor progression. Despite these findings, nothing has been described previously about the expression of miRNAs and the presence of CSCs in human TOS. Therefore, we have isolated/characterized a putative CSC cell line from human TOS (TOS-CSCs) and evaluated the expression levels of several miRNAs in TOS-CSCs using real-time quantitative assays. We show, for the first time, the existence of CSCs in human TOS, highlighting the in vitro establishment of this unique stabilized cell line and an identification of a preliminary expression of the miRNA profile, characteristic of TOS-CSCs. These findings represent an important step in the study of the biology of one of the most aggressive variants of OS and the role of miRNAs in TOS-CSC behavior.

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