Mechanism of acquired resistance to EGFR-TKI (modified from reviews of Mitsudomi and Yataba [6] and Yano [13]). (a) Survival signal through the PI3K/Akt pathway in NSCLC cells with an EGFR activating mutation (star). (b) EGFR-TKI inhibits phosphorylation of EGFR and the survival signal is shut down, leading to apoptosis of cells. (c) Secondary T790M mutation prevents binding of EGFR-TKI to EGFR, resulting in cell survival. (d) Amplified MET causes phosphorylation of ERBB3. Even when phosphorylation of EGFR is inhibited by EGFR-TKI, activation of the PI3K/Akt pathway is maintained through ERBB3. (e) HGF induces activation of the PI3K/Akt pathway through MET; this activation is independent of ERBB3 or EGFR.