Tyrosine kinase inhibitor TKI‐258 inhibits cell motility in oral squamous cell carcinoma in vitro
In malignant tumors, there is a disorganized growth, and the tumor cells get the capacity of migration and invasion, released into blood or a lymphatic vessel and overflow to a distant site, where the tumor cells proliferate, originating metastasis 2. This behavior of the cells is regulated by extracellular molecules binding to cell membrane receptors, activating one or more intracellular signaling pathways leading to activation of effector proteins 3. When a ligand binding, like growth factors, is recognize by extracellular domain, a conformational change occurs promoting receptor dimerization 6 that results in autophosphorylation of the intracellular domains and receptor activation. The phosphorylated tyrosine becomes ligand binding and activation of intracellular signaling proteins activating intracellular pathways that starts a cascade of reactions that culminates in cytoplasmic cellular responses 7.
Targeting therapies for the molecular pathways enable therapeutic advances in the treatment of neoplasias 8. The tyrosine kinase receptors are a heterogeneous group of membrane receptors that respond mainly to protein mediators such as growth factors. They have a N‐terminal extracellular domain, which binds a ligand, a field transmembrane, and an intracellular domain C‐terminal with tyrosine kinase activities 7. Among several molecules of the receptor tyrosine kinase inhibitors class, the TKI‐258 has pharmacokinetic characteristics and efficacy in various human tumor xenograft models 9. TKI‐258 is a small molecule that inhibits the autophosphorylation of tyrosine residues in receptors of growth factors: fibroblast (FGFRs), platelet‐derived (PDGF), and vascular endotelial (VEGFRs) 10. Tyrosine kinase inhibitors like TKI‐258 are small hydrophobic molecules that pass through the cell membrane and compete with adenosine triphosphate (ATP). They act directly on the ATP binding site, forming hydrogen bonds and indirectly through an allosteric site, preventing the association of ATP. Consequently, the tyrosine kinase cannot transfer phosphate to tyrosine residues, blocking signal transduction 6.
The FGFRs participate in important signaling pathways of carcinogenesis that include proliferation, survival, and cell migration 11. The PDGFRα stimulates the formation of cell protrusions and loss of stress fibers, while PDGFRβ stimulates loss of stress fibers and chemotaxis 12, cell invasion, and metastasis 13. The signaling pathway VEGF‐VEGFR operates in different tumor processes such as tumor cell migration and invasion and promotes rapid growth of tumor related to its own angiogenesis, physiological, and pathological angiogenesis 4. Although the pathways of VEGFRs seems to be more involved in angiogenesis process, some authors report their involvement in cell migration and cell invasion 14. The expression of these receptors occurs in many different types of cells and tissues 5. Receptors that are inhibited by TKI‐258 were detected in oral squamous cell carcinoma, as FGFR3b superexpression 15, PDGFRα, and PDGFRβ expression 16, also VEGFR‐1, VEGFR‐2, and VEGFR‐3 superexpression 17.
Cell lines are extensive used as a model to study molecular mechanisms and to identify diagnostic and prognostic markers for disorders like cancer. This study aimed to evaluate the effect of treatment with TKI‐258 on cell motility in SCC‐4 cell line obtained from an oral squamous cell carcinoma moderately differentiated from human tongue, using three‐dimensional assays.