fig3

Figure 3. Mechanisms of resistance to FGFR1 inhibitors. In sensitive cells, treatment with an inhibitor (e.g., BGJ398) prevents activation of PI3K. As a result AKT is not activated and FOXO3A remains unphosphorylated and can move into the nucleus where it activates PUMA. PUMA then sequesters the antiapoptotic BCL2 gene, removing its restraint on apoptosis. In the resistant cells, BGJ398 cannot bind FGFR1 and so PI3K is activated leading to activation of AKT and phosphorylation of FOXO3A which is sequestered in the cytoplasm. As a result, PUMA is not activated and so cannot interact with and suppress BCL2 and so apoptosis is suppressed.