scholarly journals Role of Endocytosis Proteins in Gefitinib-Mediated EGFR Internalisation in Glioma Cells

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3258
Author(s):  
Elisabete Cruz Da Silva ◽  
Laurence Choulier ◽  
Jessica Thevenard-Devy ◽  
Christophe Schneider ◽  
Philippe Carl ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Membrane Trafficking ◽  
Therapeutic Target ◽  
Kinase Inhibitors ◽  
Tumour Progression ◽  
Ldl Receptor ◽  
Glioma Cells ◽  
Small Gtpase ◽  
Tyrosine Kinase Receptor ◽  
Early Endosomes

EGFR (epidermal growth factor receptor), a member of the ErbB tyrosine kinase receptor family, is a clinical therapeutic target in numerous solid tumours. EGFR overexpression in glioblastoma (GBM) drives cell invasion and tumour progression. However, clinical trials were disappointing, and a molecular basis to explain these poor results is still missing. EGFR endocytosis and membrane trafficking, which tightly regulates EGFR oncosignaling, are often dysregulated in glioma. In a previous work, we showed that EGFR tyrosine kinase inhibitors, such as gefitinib, lead to enhanced EGFR endocytosis into fused early endosomes. Here, using pharmacological inhibitors, siRNA-mediated silencing, or expression of mutant proteins, we showed that dynamin 2 (DNM2), the small GTPase Rab5 and the endocytosis receptor LDL receptor-related protein 1 (LRP-1), contribute significantly to gefitinib-mediated EGFR endocytosis in glioma cells. Importantly, we showed that inhibition of DNM2 or LRP-1 also decreased glioma cell responsiveness to gefitinib during cell evasion from tumour spheroids. By highlighting the contribution of endocytosis proteins in the activity of gefitinib on glioma cells, this study suggests that endocytosis and membrane trafficking might be an attractive therapeutic target to improve GBM treatment.

scholarly journals Immunization against ROS1 by DNA Electroporation Impairs K-Ras-Driven Lung Adenocarcinomas

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 166
Author(s):  
Federica Riccardo ◽  
Giuseppina Barutello ◽  
Angela Petito ◽  
Lidia Tarone ◽  
Laura Conti ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Line ◽  
Kinase Inhibitors ◽  
Immune Memory ◽  
Tyrosine Kinase Receptor ◽  
Preclinical Model ◽  
Primary Tumors ◽  
Improve Patient Survival ◽  
Transplantable Cell ◽  
Lung Adenocarcinomas

Non-small cell lung cancer (NSCLC) is still the leading cause of cancer death worldwide. Despite the introduction of tyrosine kinase inhibitors and immunotherapeutic approaches, there is still an urgent need for novel strategies to improve patient survival. ROS1, a tyrosine kinase receptor endowed with oncoantigen features, is activated by chromosomal rearrangement or overexpression in NSCLC and in several tumor histotypes. In this work, we have exploited transgenic mice harboring the activated K-Ras oncogene (K-RasG12D) that spontaneously develop metastatic NSCLC as a preclinical model to test the efficacy of ROS1 immune targeting. Indeed, qPCR and immunohistochemical analyses revealed ROS1 overexpression in the autochthonous primary tumors and extrathoracic metastases developed by K-RasG12D mice and in a derived transplantable cell line. As proof of concept, we have evaluated the effects of the intramuscular electroporation (electrovaccination) of plasmids coding for mouse- and human-ROS1 on the progression of these NSCLC models. A significant increase in survival was observed in ROS1-electrovaccinated mice challenged with the transplantable cell line. It is worth noting that tumors were completely rejected, and immune memory was achieved, albeit only in a few mice. Most importantly, ROS1 electrovaccination was also found to be effective in slowing the development of autochthonous NSCLC in K-RasG12D mice.

scholarly journals Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways

2018 ◽  
Vol 11 (557) ◽  
pp. eaar5680 ◽  
Author(s):  
Jimmy Van den Eynden ◽  
Ganesh Umapathy ◽  
Arghavan Ashouri ◽  
Diana Cervantes-Madrid ◽  
Joanna Szydzik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Expression Profiles ◽  
Neuroblastoma Cell ◽  
Treatment Strategies ◽  
Tyrosine Kinase Receptor ◽  
Anaplastic Lymphoma ◽  
Major Interest

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is a clinical target of major interest in cancer. Mutations and rearrangements inALKtrigger the activation of the encoded receptor and its downstream signaling pathways.ALKmutations have been identified in both familial and sporadic neuroblastoma cases as well as in 30 to 40% of relapses, which makes ALK a bona fide target in neuroblastoma therapy. Tyrosine kinase inhibitors (TKIs) that target ALK are currently in clinical use for the treatment of patients with ALK-positive non–small cell lung cancer. However, monotherapy with the ALK inhibitor crizotinib has been less encouraging in neuroblastoma patients withALKalterations, raising the question of whether combinatorial therapy would be more effective. In this study, we established both phosphoproteomic and gene expression profiles of ALK activity in neuroblastoma cells exposed to first- and third-generation ALK TKIs, to identify the underlying molecular mechanisms and identify relevant biomarkers, signaling networks, and new therapeutic targets. This analysis has unveiled various important leads for novel combinatorial treatment strategies for patients with neuroblastoma and an increased understanding of ALK signaling involved in this disease.

scholarly journals Gastrointestinal Stromal Tumors Etiology, Clinical Presentation And Review Of The Literature In Greek Patients

2020 ◽  
Vol 3 (3) ◽  
pp. 01-03
Author(s):  
Panagiota Xaplanteri
Keyword(s):  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Complete Removal ◽  
Patient Treatment ◽  
Tyrosine Kinase Receptor ◽  
Stromal Tumors ◽  
The One ◽  
Nih Classification ◽  
Cells Of Cajal

Gastrointestinal stromal tumors (GIST) represent rare malignancies of mesenchymal origin that can appear at any site of the gastrointestinal tract. Their classification, patient treatment and prognosis had been a source of controversy. The biology of these tumors revealed association to the type III tyrosine kinase receptor and the KIT CD117 protein expression. GIST mesenchymal lesions derive from the interstitial cells of Cajal. Classification methods include the one by Miettinen and Lasota and the ‘‘modified NIH classification’’. The treatment of choice is surgical intervention and complete removal of the neoplasm. In patients with tumors that cannot be excised, have given metastasis, or are of high risk for metastasis, treatment also involves Kit/PDGFRA tyrosine kinase inhibitors, such as imatinib. In Greece, several cases have been described.

scholarly journals C-Met as a Key Factor Responsible for Sustaining Undifferentiated Phenotype and Therapy Resistance in Renal Carcinomas

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 272 ◽  
Author(s):  
Paulina Marona ◽  
Judyta Górka ◽  
Jerzy Kotlinowski ◽  
Marcin Majka ◽  
Jolanta Jura ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tumor Growth ◽  
Kinase Inhibitors ◽  
Mesenchymal Cell ◽  
Therapy Resistance ◽  
Cell Phenotype ◽  
Tyrosine Kinase Receptor ◽  
Met Receptor ◽  
Mesenchymal Phenotype

C-Met tyrosine kinase receptor plays an important role under normal and pathological conditions. In tumor cells’ overexpression or incorrect activation of c-Met, this leads to stimulation of proliferation, survival and increase of motile activity. This receptor is also described as a marker of cancer initiating cells. The latest research shows that the c-Met receptor has an influence on the development of resistance to targeted cancer treatment. High c-Met expression and activation in renal cell carcinomas is associated with the progression of the disease and poor survival of patients. C-Met receptor has become a therapeutic target in kidney cancer. However, the therapies used so far using c-Met tyrosine kinase inhibitors demonstrate resistance to treatment. On the other hand, the c-Met pathway may act as an alternative target pathway in tumors that are resistant to other therapies. Combination treatment together with c-Met inhibitor reduces tumor growth, vascularization and pro-metastatic behavior and results in suppressed mesenchymal phenotype and vascular endothelial growth factor (VEGF) secretion. Recently, it has been shown that the acquirement of mesenchymal phenotype or lack of cell differentiation might be related to the presence of the c-Met receptor and is consequently responsible for therapy resistance. This review presents the results from recent studies identifying c-Met as an important factor in renal carcinomas being responsible for tumor growth, progression and metastasis, indicating the role of c-Met in resistance to antitumor therapy and demonstrating the pivotal role of c-Met in supporting mesenchymal cell phenotype.

scholarly journals How to Treat a Signal? Current Basis for RET-Genotype-Oriented Choice of Kinase Inhibitors for the Treatment of Medullary Thyroid Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Hugo Prazeres ◽  
Joana Torres ◽  
Fernando Rodrigues ◽  
Joana P. Couto ◽  
João Vinagre ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tyrosine Kinase ◽  
Intracellular Signaling ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Age Of Onset ◽  
Point Mutations ◽  
Tyrosine Kinase Receptor ◽  
Intracellular Signaling Pathways ◽  
Activating Mutation

The significance ofRETin thyroid cancer comes from solid evidence that, when inherited, anRETactivating mutation primes C-cells to transform into medullary carcinomas. Moreover, environmental exposure to radiation also induces rearranged transforming RET “isoforms” that are found in papillary thyroid cancer. TheRETgene codes for a tyrosine kinase receptor that targets a diverse set of intracellular signaling pathways. The nature ofRETpoint mutations predicts differences in the mechanisms by which the receptor becomes activated and correlates with different forms of clinical presentation, age of onset, and biological aggressiveness. A number of RET-targeting Tyrosine Kinase Inhibitors (TKIs) are currently undergoing clinical trials to evaluate their effectiveness in the treatment of thyroid cancer, and it is conceivable that the RET genotype may also influence response to these compounds. The question that now emerges is whether, in the future, the rational for treatment of refractory thyroid cancer will be based on the management of an abnormal RET signal. In this paper we address the RET-targeting TKIs and review studies about the signaling properties of distinct RET mutants as a means to predict response and design combinatorial therapies for the soon to be available TKIs.

Tyrosine kinase receptor alteration of renal vasoconstriction in rats is sex- and age-related

2012 ◽  
Vol 90 (10) ◽  
pp. 1372-1379 ◽  
Author(s):  
John C. Passmore ◽  
John T. Fleming ◽  
Suresh C. Tyagi ◽  
Jeff C. Falcone
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Young Male ◽  
Female Rats ◽  
Male Rats ◽  
Male Rat ◽  
Tyrosine Kinase Receptor ◽  
Middle Aged ◽  
Male And Female Rats ◽  
Age Related

Male rat renal blood vessels undergo reduced contraction to norepinephrine with aging. There is a greater renal vascular impairment in male compared with female rats. We investigated specific tyrosine kinase receptor inhibition of renal interlobar artery responsiveness to phenylephrine in male and female rats at specifically designated ages. Vessels from young male rats contracted much less to phenylephrine when the vessels were pretreated with the tyrosine kinase inhibitors Lavendustin A, HNMPA-(AM)3, or AG1478. Vessels from adult female rats pretreated with Lavendustin A showed no difference in contraction from control, but did demonstrate a slightly reduced contraction when pretreated with AG1478. Middle-aged male rat vessels treated with Lavendustin A demonstrated no inhibition, but the insulin and epidermal growth factor receptor (EGFR) antagonists both induced a decline in contraction. Vessels from aged male rats demonstrated no effect related to the 3 pretreatments. Middle-aged and aged female rats pretreated with any inhibitor demonstrated no inhibitor-dependent alterations. We conclude that maximum contraction of interlobar arteries from adult male rats is reduced when tyrosine kinase receptor activity is reduced. Female rats demonstrated much less inhibitor-related change of contraction.

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