Fig. 3

Mechanisms of alternative signaling activation induced FGFR-TKI resistance. FGFR signaling pathway regulation networks are shown in black arrows. Mechanisms of FGFR-TKI resistance caused by feedback signaling activation are shown. a Loss of PTEN up-regulates the expression of PIK kinase via interfering with the conversion of PIP2 to PIP3 and abortively activates AKT; b inactivation of PHLDA1 continuously activates AKT signaling by competitively binding AKT with PIP3; c inactivation of RASA1 directly activates RAS-MAPK pathway through regulating the active transformation of RAS; d NRAS amplification and DUSP6 deletion stimulate activation of the MAPK pathway; e alternative activation of cytomembrane localized kinases, such as EGFR, MET and ErbB3, bypass FGFR signaling pathway