Combined Inhibition of IGF-1R/IR and Src Family Kinases Enhances Antitumor Effects in Prostate Cancer by Decreasing Activated Survival Pathways
Figure 5
Dasatinib and BMS-754807 have different effects on tumorigenic properties of PCa cells.
Circulating IGF-1 from multiple sources (bone, tumor cells, adipocytes, etc.) binds to IGF-1R, which leads to downstream activation of Akt and suppression of apoptosis. BMS-754807 inhibits IGF-1R phosphorylation and thus leads to partial inhibition of Akt1 and Akt2. While Akt2 phosphorylation is Src independent, Akt1 phosphorylation is also Src mediated, so full blockade is dependent on dual inhibition of Src and IGF-1R. Activation of IGF-1R, but also of many other cell surface receptors (integrins, vascular endothelial growth factor-receptor [VEGF-R], Axl, c-Met, etc.), involves Src activation, which increases PCa cell motility, migration, and invasion. Dasatinib inhibits Src phosphorylation, thereby decreasing invasive/migratory properties of PCa cells. Since Akt is activated by both IGF-1R and Src, blockade of either pathway alone will only partially inhibit Akt phosphorylation, whereas the dual blockade almost completely abrogates Akt phosphorylation. FAK: focal adhesion kinase.