The development of resistance to epidermal growth factor receptor tyrosine 
kinase inhibitors (EGFR-TKI) seems almost inevitable, even in patients with lung 
cancer that initially respond well to EGFR-TKIs. MET amplification was recently 
found to be a mechanism of escape from the anticancer effect of EGFR inhibitors. 
In the present study, we investigated the means whereby MET affects sensitivity 
to EGFR-TKIs in PC-9 cells. Gefitinib- or erlotinib-resistant sublines were 
established by exposing the parental PC-9 cell line to chronic, repeated 
treatments with these drugs. These resistant sublines showed more than 100-fold 
more resistance to gefitinib and erlotinib and acquired cross-resistance to 
other EGFR-TKIs. The T790M EGFR mutation was found by pyrosequencing, and this 
seemed to be the cause of drug resistance. Resistant cells also showed MET 
activation, although gene amplification was not detected. Furthermore, the 
induction of MET activity was not found to be associated with sensitivity to 
EGFR-TKIs. Interestingly, increased passage number without exposure to gefitinib 
or erlotinib caused MET activation, but this did not affect sensitivity to 
EGFR-TKIs. In addition, hepatocyte growth factor was found to block the ability 
of EGFR-TKIs to inhibit MET activation. However, sustained MET activation by 
hepatocyte growth factor did not modulate the cellular effects of gefitinib or 
erlotinib. Rather, activated MET enhanced migration and invasion abilities. 
Summarizing, MET activation may be acquired during cancer cell proliferation and 
enhances migratory and invasive abilities without affecting cellular sensitivity 
to EGFR-TKIs. Accordingly, the present study suggests that MET activation caused 
by factors other than MET gene amplification is not a suitable surrogate marker 
of resistance to EGFR-TKIs.