scholarly journals Tyrosine kinases in etiopathogenesis and therapy of malignant diseases: c-kit activating mutations

2010 ◽  
Vol 63 (5-6) ◽  
pp. 380-386
Author(s):  
Karmen Stankov ◽  
Gordana Bogdanovic ◽  
Stevan Popovic
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Malignant Disease ◽  
Therapeutic Response ◽  
Kinase Inhibitors ◽  
New Technologies ◽  
Cancer Therapeutics ◽  
Activating Mutations ◽  
Gene Expression Levels

Introduction. In the last 15 years, the introduction of molecular biology methods and techniques for identifying mutations and measuring gene expression levels of mutated genes since recently, have enabled precise molecular diagnostics, classification and assessment of prognosis and therapeutic response of malignant disease to specific therapies. The increased knowledge of the cancer genome and the introduction of multiple new technologies in cancer research have significantly improved the drug discovery process, leading to key success in targeted cancer therapeutics, including tyrosine kinase inhibitors. Tyrosine kinase inhibitors are the molecular targeted neoadjuvant and adjuvant therapy of various malignancies. Many more results which are expected from ongoing trials are necessary to specify the appropriate dosages, stages at which to start the treatment, and which therapeutic combinations to apply.

scholarly journals Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

2021 ◽  
Vol 22 (2) ◽  
pp. 493
Author(s):  
Christos Vallilas ◽  
Panagiotis Sarantis ◽  
Anastasios Kyriazoglou ◽  
Evangelos Koustas ◽  
Stamatios Theocharis ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Cancer Therapeutics ◽  
Gastrointestinal Neoplasms ◽  
Mesenchymal Tumors ◽  
Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

scholarly journals Combating Acquired Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

2015 ◽  
pp. e165-e173 ◽  
Author(s):  
Christine M. Lovly
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Initial Response ◽  
In Vitro Models ◽  
Tumor Biopsy

The prospective identification and therapeutic targeting of oncogenic tyrosine kinases with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment for patients with non–small cell lung cancer (NSCLC). TKI therapy frequently induces dramatic clinical responses in molecularly defined cohorts of patients with lung cancer, paving the way for the implementation of precision medicine. Unfortunately, acquired resistance, defined as tumor progression after initial response, seems to be an inevitable consequence of this treatment approach. This brief review will provide an overview of the complex and heterogeneous problem of acquired resistance to TKI therapy in NSCLC, with a focus on EGFR-mutant and ALK-rearranged NSCLC. In vitro models of TKI resistance and analysis of tumor biopsy samples at the time of disease progression have generated breakthroughs in our understanding of the spectrum of mechanisms by which a tumor can thwart TKI therapy and have provided an important rationale for the development of novel approaches to delay or overcome resistance. Numerous ongoing clinical trials implement strategies, including novel, more potent TKIs and rational combinations of targeted therapies, some of which have already proven effective in surmounting therapeutic resistance.

Efficacy of EGFR tyrosine kinase inhibitors in patients having EGFR-activating mutations with or without BIM polymorphisms

2020 ◽  
Vol 86 (4) ◽  
pp. 517-525
Author(s):  
Ryo Ariyasu ◽  
Noriko Yanagitani ◽  
Kenichi Tadokoro ◽  
Toshikazu Yamaguchi ◽  
Ken Uchibori ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Activating Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors

scholarly journals An Inducible TGF-β2-TGFβR Pathway Modulates the Sensitivity of HNSCC Cells to Tyrosine Kinase Inhibitors Targeting Dominant Receptor Tyrosine Kinases

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0123600 ◽  
Author(s):  
Emily K. Kleczko ◽  
Jihye Kim ◽  
Stephen B. Keysar ◽  
Lydia R. Heasley ◽  
Justin R. Eagles ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Receptor Tyrosine Kinases

scholarly journals Targeting Tumor-Induced Immunosuppression Using Conventional Cancer Therapeutics

2021 ◽  
Vol 9 (12) ◽  
Author(s):  
Emma Eriksson ◽  
Tanja Lövgren ◽  
Angelica Loskog
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Suppressor Cells ◽  
Cancer Therapeutics ◽  
Phase Iii ◽  
Current View ◽  
T Cell Therapy ◽  
Combination Treatments

Immunosuppression remains a challenge in the immunotherapy field and needs to be combated to increase survival of patients suffering from cancer. There have been no phase III trials that have in an organized, statistically reliable setting compared immunotherapy outcome with or without so called preconditioning, or metronomic conditioning, in randomized settings. The current view on preconditioning is that it may be used both to reduce tumor load and to reduce suppressive immune cells prior to immunotherapy. For combination treatments, immunotherapy such as checkpoint blockade has shown benefit in combination with chemotherapy even if the major goals of those studies may not have been to condition the patient for a better immune response due to reduced immunosuppression. Nevertheless, there is a need to further enhance the promising effect of cancer immunotherapy. We argue herein that there are several interesting conventional cancer therapeutics to explore for combinational use with immunotherapy to enhance response rates and achieve a longer overall survival of patients. This review will discuss mechanisms of conventional cancer therapeutics of interest for combination therapy. For example, gemcitabine and several tyrosine kinase inhibitors have profound effect on myeloid-derived suppressor cells while tyrosine kinase inhibitors can enhance T cell infiltration into tumors likely due to increased chemokine signaling. Further, cyclophosphamide is well known for its capacity to reduce Tregs and is used to precondition patients prior T cell therapy. How to combine these agents with immunotherapy to further increase patient survival is an important next step in the immunotherapeutic field.

scholarly journals Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
D. Samuel Metibemu ◽  
O. Adeboye Akinloye ◽  
A. Jamiu Akamo ◽  
D. Ajiboye Ojo ◽  
O. Tolulope Okeowo ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Conformational Changes ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Receptor Tyrosine Kinases ◽  
Acquired Resistance ◽  
Cellular Growth ◽  
Tyrosine Kinase Domain

Abstract Background Receptor tyrosine kinases (RTKs) are signaling enzymes responsible for the transfer of Adenosine triphosphate (ATP) γ-phosphate to the tyrosine residues substrates. RTKs demonstrate essential roles in cellular growth, metabolism, differentiation, and motility. Anomalous expression of RTK customarily leads to cell growth dysfunction, which is connected to tumor takeover, angiogenesis, and metastasis. Understanding the structure, mechanisms of adaptive and acquired resistance, optimizing inhibition of RTKs, and eradicating cum minimizing the havocs of quiescence cancer cells is paramount. MainText Tyrosine kinase inhibitors (TKIs) vie with RTKs ATP-binding site for ATP and hitherto reduce tyrosine kinase phosphorylation, thus hampering the growth of cancer cells. TKIs can either be monoclonal antibodies that compete for the receptor’s extracellular domain or small molecules that inhibit the tyrosine kinase domain and prevent conformational changes that activate RTKs. Progression of cancer is related to aberrant activation of RTKs due to due to mutation, excessive expression, or autocrine stimulation. Conclusions Understanding the modes of inhibition and structures of RTKs is germane to the design of novel and potent TKIs. This review shed light on the structures of tyrosine kinases, receptor tyrosine kinases, tyrosine kinase inhibitors, minimizing imatinib associated toxicities, optimization of tyrosine kinase inhibition in curtailing quiescence in cancer cells and the prospects of receptor tyrosine kinase based treatments.

Identifying resistance biomarkers against five clinically approved tyrosine kinase inhibitors in 45 cell lines.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21005-e21005
Author(s):  
Zsófia Pénzváltó ◽  
Bálint Tegze ◽  
Attila Marcell Szasz ◽  
Reinhold Schäfer ◽  
Balazs Gyorffy
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Resistance Index ◽  
Cancer Therapeutics ◽  
Immunohistochemical Analysis ◽  
Clinical Samples

e21005 Background: Clinical studies show low overall response rates of 10-47% to targeted cancer therapeutics. Our aim was to identify new biomarkers for predicting sensitivity against five already approved tyrosine kinase inhibitors. Methods: Sensitivity to sunitinib, erlotinib, lapatinib, sorafenib and gefitinib were tested in 45 cancer cell lines, and a resistance index was calculated for each cell line. The gene expression profiles (data were obtained by interrogating the raw microarray data of the caArray database) in the subset of resistant vs. sensitive cell lines were compared for each drug. Feature selection was carried out using significance analysis of microarrays and rank products. The results were validated by qPCR in the cell lines and - in case of four sunitinib resistance associated genes - in clinical samples by immunohistochemistry. Results: A set of 63 genes was identified as associated with resistance against the examined drugs. Overall classification accuracy of the prediction was 92.8% in a leave-one-out cross validation using prediction analysis of microarrays. The expression of the genes was validated by qPCR in the cell lines. The results confirmed 45/63 of the microarray-based resistance associated genes and 7/32 of literature based genes. All together 48 sunitinib-treated metastatic renal cell carcinomas were collected. The immunohistochemical analysis in these confirmed the correlation of the expression of RAB17, LGALS8, and EPCAM with overall survival. Conclusions: We identified new predictive biomarker candidates for five tyrosine kinase inhibitors, and validated a set of sunitinib resistance associated genes in an independent patient cohort.

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