scholarly journals Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

10.3791/57779 ◽  
2018 ◽  
Author(s):  
Katrin Tiemann ◽  
Carolina Garri ◽  
Jeffrey Wang ◽  
Lauren Clarke ◽  
Kian Kani
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Signal Transduction Pathways ◽  
Antibody Arrays

Tyrosine kinase inhibitors and signal transduction modulators: Rationale and current status as chemopreventive agents for prostate cancer

Urology ◽  
2001 ◽  
Vol 57 (4) ◽  
pp. 77-80 ◽  
Author(s):  
Raymond C Bergan ◽  
Doyle H Waggle ◽  
Stephen K Carter ◽  
Ivan Horak ◽  
William Slichenmyer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Current Status ◽  
Chemopreventive Agents

scholarly journals Integrin function: molecular hierarchies of cytoskeletal and signaling molecules.

1995 ◽  
Vol 131 (3) ◽  
pp. 791-805 ◽  
Author(s):  
S Miyamoto ◽  
H Teramoto ◽  
O A Coso ◽  
J S Gutkind ◽  
P D Burbelo ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Signaling Molecules ◽  
Cytochalasin D ◽  
Integrin Receptors ◽  
Jnk Pathway ◽  
Herbimycin A ◽  
Rapid Activation

Integrin receptors play important roles in organizing the actin-containing cytoskeleton and in signal transduction from the extracellular matrix. The initial steps in integrin function can be analyzed experimentally using beads coated with ligands or anti-integrin antibodies to trigger rapid focal transmembrane responses. A hierarchy of transmembrane actions was identified in this study. Simple integrin aggregation triggered localized transmembrane accumulation of 20 signal transduction molecules, including RhoA, Rac1, Ras, Raf, MEK, ERK, and JNK. In contrast, out of eight cytoskeletal molecules tested, only tensin coaccumulated. Integrin aggregation alone was also sufficient to induce rapid activation of the JNK pathway, with kinetics of activation different from those of ERK. The tyrosine kinase inhibitors herbimycin A or genistein blocked both the accumulation of 19 out of 20 signal transduction molecules and JNK- and ERK-mediated signaling. Cytochalasin D had identical effects, whereas three other tyrosine kinase inhibitors did not. The sole exception among signaling molecules was the kinase pp125FAK which continued to coaggregate with alpha 5 beta 1 integrins even in the presence of these inhibitors. Tyrosine kinase inhibition also failed to block the ability of ligand occupancy plus integrin aggregation to trigger transmembrane accumulation of the three cytoskeletal molecules talin, alpha-actinin, and vinculin; these molecules accumulated even in the presence of cytochalasin D. However, it was necessary to fulfill all four conditions, i.e., integrin aggregation, integrin occupancy, tyrosine kinase activity, and actin cytoskeletal integrity, to achieve integrin-mediated focal accumulation of other cytoskeletal molecules including F-actin and paxillin. Integrins therefore mediate a transmembrane hierarchy of molecular responses.

Inhibition of PI3K/Akt and Erk Signaling Pathways by BCR-ABL Tyrosine Kinase Inhibitors up-Regulates the Immunosuppressive Receptor Osteoactivin in Monocyte-Derived Dendritic Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1050-1050
Author(s):  
Michael Gutknecht ◽  
Simone Joas ◽  
Lothar Kanz ◽  
Helmut R Salih ◽  
Susanne M Rittig ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Dendritic Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Western Blotting ◽  
Kinase Inhibitors ◽  
Type I ◽  
Blood Monocytes ◽  
Abl Tyrosine Kinase

Abstract Abstract 1050 Osteoactivin (GPNMB, DC-HIL) is a type I transmembrane glycoprotein that is expressed in dendritic cells (DC). Osteoactivin/syndecan-4 (SD-4) interaction was previously shown to inhibit T cell activation by antigen-presenting cells. We recently demonstrated that exposure of human peripheral blood monocytes to IL-10 or pharmacological levels of the BCR-ABL tyrosine kinase inhibitors (TKI) imatinib or nilotinib during differentiation into monocyte-derived DC (moDC) causes up-regulation of osteoactivin at the transcript and protein level in vitro (Schwarzbich et al., 2012). Here we aimed to elucidate the molecular mechanisms responsible for osteoactivin up-regulation in moDC upon exposure to IL-10 or TKI (imatinib, nilotinib). moDC were generated from blood monocytes by plastic adherence and exposure to GM-CSF and IL-4. Every second day, starting from the first day of culture, IL-10 or TKI were added to the culture medium. Alternatively, specific inhibitors of PI3K, Akt, Erk and/or C-Raf signal transduction pathways were added to the cell cultures. Cells were harvested on day 7 of culture for immunophenotyping and osteoactivin expression analysis using FACS, western-blotting and real-time qRT-PCR. The expression and activity of signal transduction molecules was monitored by western-blotting and pathway protein arrays. Analysis of moDC function was performed using mixed lymphocyte reactions (MLR). Our in vitro analysis revealed that IL-10 and BCR-ABL TKI inhibit the PI3K/Akt and, to a lesser extent, the Erk pathway in moDC. Specific inhibition of these signal transduction cascades resulted in profound up-regulation of osteoactivin expression in moDC confirming the involvement of PI3K/Akt and Erk in the regulation of osteoactivin expression. In line, TKI treatment and inhibition of PI3K/Akt and Erk comparably affected the phenotype of moDC. Moreover, the inhibition of these signalling cascades resulted in reduced stimulatory capacity of moDC in MLR with allogenic T cells, and this could be restored by addition of blocking osteoactivin antibody. Our data reveal that TKI exert immunosuppressive effects in moDC by interfering with pathways involved in IL-10 receptor signaling. Inhibition of osteoactivin expression or function may thus constitute a promising strategy in combinatory approaches using TKI and DC-based immunotherapy and may enhance the efficacy of immunotherapeutic interventions in cancer patients. Disclosures: No relevant conflicts of interest to declare.

Side effects of tyrosine kinase inhibitors (TKIs) on bone remodelling

2012 ◽  
Vol 224 (03) ◽  
Author(s):  
JT Tauer ◽  
A Ulmer ◽  
LC Hofbauer ◽  
M Suttorp
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Bone Remodelling

A framework for risk stratification in EGFR+ lung adenocarcinoma treated with tyrosine kinase inhibitors

2019 ◽  
Author(s):  
P Christopoulos ◽  
M Kirchner ◽  
F Bozorgmehr ◽  
N Magios ◽  
AL Volckmar ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Tyrosine Kinase ◽  
Lung Adenocarcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors
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