The PI3K inhibitors, GSK2126458 and PF04691502, strongly inhibited the phosphorylation of Akt. These agents significantly suppressed the proliferation of wild-type EGFR A549 cells...The MEK inhibitors, AZD-8330 and TAK-733, also significantly inhibited the proliferation of A549 cells....Combined use of EGFR-TKI and MET inhibitors or inhibition of downstream signaling molecules might be a better second or third line choice for a group of patients with advanced lung cancer harboring wild-type EGFR.