So the inhibitory response of p Src, p FAK and p Akt to dasatinib might also give guidance for predicting response, while they have been more variable than baseline t Src. Important correlation among IC50 and expression of t Src may very well be proven in majorities of cell lines, primarily in gefitinib resistant cell lines. How ever, there were exceptions, this kind of as Huh seven cells, Src dependant signal pathway was not an essential determin ant of cell proliferation, motility and invasion in Huh seven cells which was resistant to dasatinib but showed p Src in hibition by dasatinib. Interestingly, we observed that higher ra tio of p Src t Src was significantly associated with less resistant to dasatinib in all 6 dasatinib resistant cell lines. This implied that the mechanism of action of dasatinib in sensitive cell lines may perhaps be different from that of resistant cell lines.
Moreover, there have been distinctions among other cell lines within the inhibition of p Src, p FAK, p Akt, cell ad hesion, migration and invasion by dasatinib. Therefore, we demonstrated the heterogeneity of HCC tumor biology and the will need for individualized treatment method. Biomarkers may perhaps supply guidance for selecting appropriate treatment for the proper patient. It can require prospective studies to validate our site our findings. From the research of bination of dasatinib and erlotinib in sufferers with innovative NSCLC, reduction of vascular endothelial growth component was correlated with illness management However, a phase II examine of sin gle agent dasatinib in advanced NSCLC showed that nei ther activation of SFK nor EGFR and Kras mutations in tumor tissue predicted response to dasatinib No clin ical outcomes are available but from studying dasatinib in ad vanced HCC sufferers. Src interacts with FAK to play a vital position in tumor cell migration and invasion.
On intergrin engagement or stimulation of EGF or PDGF receptors, FAK autophospho rylates at pTyr397, building a high affinity binding web site for DCC-2036 Src, the association involving Src and FAK resulted in acti vation of Src and phosphorylation of FAK at Tyr 576, 577, 861 and 925. The Src FAK plex phosphorylated quite a few other focal adhesion proteins and activated other intra cellular signaling pathway This interaction involving Src and FAK has been shown to regulate the two cell motility and invasion Concerning our effects, in 56% studied HCC cell lines, dasatinib inhibits the exercise of Src to cut back phosphorylation of FAK. Inhibition of FAK at Tyr576 577 was strongly correlated with HCC cell adhesion, migration and invasion. For 78% of studied HCC cell lines, reduction of activated FAK576 577 was drastically correlated using the dasatinib sensitivity. As a result the SFK FAK signaling pathway plays a crucial part in cell adhesion, migration and invasion.