Therapies　targeting　epidermal　growth　factor　receptor　(EGFR)　can　effectively　treat　with　non-small　cell　lung　cancer　(NSCLC),　but　NSCLC＇s　drug　resistance　makes　it　intractable.　Herein,　we　showed　that　RU486　metabolite　metapristone　inhibited　the　proliferation　of　various　NSCLC　cell　lines　with　either　wild　(A549,　H1299,　H520)　or　mutated　EGFR　(H1975,　HCC827).　The　suppression　was　resulted　from　inhibition　by　metapristone　of　EGFR　signaling　pathways　through　down-regulating　the　EGFR,　PTEN,　as　well　as　AKT　and　ERK　proteins.　In　addition,　metapristone　inhibited　anti-apoptotic　marker　Bcl-2,　and　activated　pro-apoptotic　key　signaling　proteins　caspase-3,　and　poly　(ADP-ribose)　polymerase.　Metapristone　induced　A549　and　H1975　cell　cycle　via　arrest　at　the　G0-G1　stage.　What＇s　more,　metapristone　inhibited　the　growth　of　NSCLC　xenografts　in　BALB/c　nude　mice　through　decreasing　the　expression　of　tumor　growth　biomarkers　PCNA　and　EGFR.　Taken　together,　the　present　study　demonstrated　that　metapristone　suppressed　NSCLC　proliferation　by　promoting　apoptosis　via　decrease　the　cellular　EGFR-mediated　PI3K/AKT　pathways.　The　results　suggest　metapristone　a　new　treatment　for　EGFR-overexpressed　NSCLC.　©　Shao　et　al.