One of the main mechanisms of secondary resistance in patients treated
with tyrosine kinase inhibitors is acquisition of new inhibitor - resistant mutations.
DDRs inhibition
with a tyrosine kinase inhibitor appears to insulate the brain via blood - brain barrier repair, which prevents harmful immune cells that circulate in the body from getting into the brain where they can indiscriminately attack and kill healthy and sick neurons, like those that have been unable to perform autophagy to «take out their trash,» says Moussa.
Not exact matches
The estimation of EGFR mutation status is essential for the identification of non-small cell lung carcinoma (NSCLC) patients who may benefit from treatment
with EGFR
tyrosine kinase inhibitors (TKIs), and hence for improving therapeutic efficacy.
For example, epidermal growth factor (EGFR) mutations may result in sensitivity to drugs that are EGFR
tyrosine kinase inhibitors (TKIs), such as erlotinib or gefitinib, whereas individuals
with the EGFR T790M mutation are more resistant to these drugs.
EGFR
tyrosine kinase inhibitor (TKI) therapy is approved for EGFR activating mutation positive patients
with advanced NSCLC, but the standard for determining mutation status is
with DNA derived directly from tumor tissue, which can be limited or not available.
Among patients
with advanced non-small cell lung cancer without a mutation of a certain gene (EGFR), conventional chemotherapy, compared
with treatment using epidermal growth factor receptor
tyrosine kinase inhibitors, was associated
with improvement in survival without progression of the cancer, but not
with overall survival, according to a study in the April 9 issue of JAMA.
Epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitors (TKIs) are the preferred treatment option for patients
with advanced non-small cell lung cancer (NSCLC) who have mutations in the EGFR gene.
Approximately 10 - 15 % of Caucasian and 30 - 35 % of Asian patients
with NSCLC have a mutation in the epidermal growth factor receptor (EGFR), which can be successfully targeted
with EGFR inhibitors called
tyrosine kinase inhibitors (TKI), such as erlotinib, gefitinib and afatinib.
If this is true, then immunocheckpoint blockade combination
with EGFR
tyrosine kinase inhibitors is a major path towards improving outcome of patients who have EGFR - mutant non-small-cell lung cancer.»
During the early years of my PhD studies, I was very fascinated by the exciting discoveries in the field of signal transduction, in particular how receptor
tyrosine kinases are activated to transmit their signals and how protein complexes are formed through defined protein folds (domains) interacting
with specific cellular targets.
We review progress
with the receptor
tyrosine kinases (growth factor receptors EGFR, VEGFR, and FGFR) and nonreceptor
tyrosine kinases (Bcr - Abl), where advances have been made
with cancer therapeutic agents such as Herceptin and Gleevec.
Gene expression in papillary thyroid carcinomas,
with special reference to
tyrosine kinase receptors and growth factors.
A class of oral specialty drugs,
tyrosine kinase inhibitors (TKIs), has revolutionized the treatment of CML, largely transforming it into a chronic condition and enabling many patients to have a near - normal lifespan, particularly when compared to a median survival of less than three years
with prior therapies.
Chan AC, Iwashima M, Trck CW, Weiss A. ZAP - 70: a 70kd protein -
tyrosine kinase that associates
with the TCRzeta chain.
Scanning electron micrograph of the coronary microvasculature of a mouse that has been treated
with a small molecule
tyrosine kinase inhibitor of platelet - derived growth factor receptor beta.
In addition to being integral to cell biology,
tyrosine kinases also present targets for new anticancer therapies: One of the most highly touted, rationally designed anticancer compounds, Gleevec, inhibits an oncogenic
tyrosine kinase whose aberrant activity fuels the rampant growth of cells in patients
with chronic myeloid leukemia.
Another focus was the differential sensitivity of different mutations towards inhibition
with specific
tyrosine kinase inhibitors (5).
Azoospermia in mice
with targeted disruption of the Brek / Lmtk2 (brain - enriched
kinase / lemur
tyrosine kinase 2) gene.
Expression of the receptor
tyrosine kinase Tie2 in neoplastic glial cells is associated
with integrin beta1 - dependent adhesion to the extracellular matrix.
We investigated the role of the cytoplasmic
tyrosine kinase JAK2 in patients
with a myeloproliferative disorder.
Patients
with chronic myeloid leukemia in the blast phase pose a significant therapeutic challenge and have poor survival, even in the
tyrosine kinase inhibitor era, according to a new study.
The US Food and Drug Administration (FDA) recently approved the oral Bruton
tyrosine kinase (BTK) inhibitor ibrutinib for the treatment of patients
with relapsed or refractory marginal zone lymphoma who require systemic therapy and have had at least one prior anti-CD20 therapy.
Currently, 31
tyrosine kinase inhibitors are FDA approved for human therapy,
with many more in clinical trials.
Mutations in fms related
tyrosine kinase 3 (FLT3) gene are the most common mutations found in acute myeloid leukemia (AML) and are characterized by an aggressive phenotype
with a high prevalence of relapse.
Also, genes that code for receptor
tyrosine kinases, a family of receptors on the surface of cells, may rearrange to form multiple distinct gene fusion partners, as evidenced in an article by Kulkarni, et al, on a translational study involving a patient who developed a BRAF fusion following treatment
with a BRAF inhibitor1.
These mutant
kinases are attractive therapeutic targets, as demonstrated by the efficacy of imatinib in BCR - ABL — positive chronic myelogenous leukemia (CML), 5 as well as in MPD associated
with activating alleles involving PDGFRA or PDGFRB.2, 6,7 In addition, activating mutations in the FLT3 receptor
tyrosine kinase are the most common genetic event in acute myeloid leukemia (AML), and specific inhibitors of the FMS - like
tyrosine kinase 3 (FLT3) have entered late - stage clinical trials.8 Although mutations in
tyrosine kinases and in other genes have been identified in a subset of MPD and AML, in many cases the genetic events that contribute to the molecular pathogenesis of these diseases remain unknown.
In 2005, the identification of an activating mutation in JAK2 (the V617F mutation) as a STAT5 - activating and disease - causing genetic alteration in a significant proportion of patients
with myeloproliferative neoplasms (MPNs) has emphasized the oncogenic role of the JAK
tyrosine kinases in hematologic malignancies.2 — 5 JAK2 is a member of the Janus
tyrosine kinase family comprising three other mammalian non-receptor
tyrosine kinases (JAK1, JAK3 and TYK2) that associate
with cytokine receptors lacking intrinsic
kinase activity to mediate cytokine - induced signal transduction and activation of STAT transcription factors.6 All JAKs share a similar protein structure and contain a
tyrosine kinase domain at the C - terminus flanked by a catalytically inactive pseudokinase domain
with kinase - regulatory activity, by an atypical SH2 domain and by a FERM domain that mediates association to the membrane - proximal region of the cytokine receptors.7, 8 Soon after the discovery of JAK2 V617F, we and others described that activating JAK1 mutations are relatively common in adult patients
with T - cell acute lymphoblastic leukemia (ALL) and participate in ALL development allowing for constitutive activation of STAT5.9 — 11 Several STAT5 - activating JAK1 mutations were also reported in AML and breast cancer patients.10
Recently, we and others identified a recurrent somatic activating mutation in the JAK2
tyrosine kinase in polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia
with myelofibrosis (MMM).9 - 13 This mutation results in a valine to phenylalanine substitution at codon 617 within the Jak homology domain 2 (JH2) pseudokinase domain of Janus
kinase 2 (JAK2).
In addition, at least some Eph receptors can also signal through non-canonical mechanisms that are independent of ligand binding and
kinase activity, for example through interplay
with other receptor
tyrosine kinase families and
with serine / threonine
kinases.
We believe these observations warrant a comprehensive search for activated
tyrosine kinases in MPD and AML, as there are likely additional unidentified genetic events
with biologic and therapeutic significance.
Recently, we and others identified a single recurrent somatic activating mutation (JAK2V617F) in the Janus
kinase 2 (JAK2)
tyrosine kinase in the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myeloid metaplasia
with myelofibrosis.
For example, our past work showed that two conserved
tyrosine phosphorylation sites in the juxtamembrane segment of the Eph receptors not only mediate association
with binding partners but also regulate receptor
kinase activity.
External cues act on
tyrosine kinase proteins embedded in the cell membrane to induce a cascade of signals
with a vital role in regulating cell proliferation.
32) Kubo T, Yamamoto H, Lockwood WW, Fujii T, Ouchida M, Soh J, Takigawa J, Kiura K, Shimizu K, Date H, Minna JD, Lam WL, Gazdar AF, Toyooka S (2009) MET gene amplification or EGFR mutation activate MET in lung cancers untreated
with EGFR
tyrosine kinase inhibitors.
Inform and educate clinicians as to updates and revisions of their Molecular testing Guideline for the Selection of Lung cancer Patients for Treatment
with Targeted
Tyrosine Kinase Inhibitors.
Erlotinib, an EGFR
tyrosine kinase inhibitor, has proven to be an effective agent in patients
with mutations in the EGFR gene, but its efficacy in wild - type EGFR patients was unclear.
In fact, numerous animal studies show that soy isoflavones interfere
with an enzyme called
tyrosine kinase in the hippocampus, a brain region involved
with learning and memory.
Twelve - hour exposure of 3T3 - L1 adipocytes to H (2) O (2) or TNF - alpha resulted in the increase of c - Jun NH (2)- terminal
kinase (JNK) activation and insulin receptor substrate 1 (IRS1) serine 307 phosphorylation, concomitantly
with the decrease in insulin - stimulated IRS1
tyrosine phosphorylation and cellular glucose uptake.
METHODS: We treated 3T3 - L1 adipocytes
with 2.5 mmol / l R (+) alpha - lipoic acid for 2 to 60 min, followed by assays of: 2 - deoxyglucose uptake; glucose transporter 1 and 4 (GLUT1 and GLUT4) subcellular localization;
tyrosine phosphorylation of the insulin receptor or of the insulin receptor substrate - 1 in cell lysates; association of phosphatidylinositol 3 -
kinase activity
with immunoprecipitates of proteins containing phosphotyrosine or of insulin receptor substrate - 1 using a in vitro
kinase assay; association of the p85 subunit of phosphatidylinositol 3 -
kinase with phosphotyrosine proteins or
with insulin receptor substrate - 1; and in vitro activity of immunoprecipitated Akt1.
Multi-center, placebo - controlled, double - blind, randomized study of oral toceranib phosphate (SU11654), a receptor
tyrosine kinase inhibitor, for the treatment of dogs
with recurrent (either local or distant) mast cell tumor following surgical excision.