Lay　abstract　The　TMEM176A　gene　is　often　methylated　in　human　lung　cancer　by　addition　of　a　methyl　group　to　the　gene　promotor　region.　This　regulates　the　expression　of　TMEM176A.　We　found　that　TMEM176A　suppressed　lung　cancer　growth　both　in　vitro　and　in　vivo　by　inhibiting　ERK　signaling.　Methylation　of　TMEM176A　sensitized　H1299　and　H23　cells　to　AZD0156,　an　ATM　kinase　inhibitor　used　to　induce　tumor　cell　death.　Reexpression　of　TMEM176A　reduced　the　sensitivity　of　these　cells　to　AZD0156.　Methylation　of　TMEM176A　is　a　novel　synthetic　lethality　therapeutic　marker　of　AZD0156　in　human　lung　cancer.　Aim:　The　role　of　TMEM176A　methylation　in　lung　cancer　and　its　therapeutic　application　remains　unclear.　Materials　and　methods:　Nine　lung　cancer　cell　lines　and　123　cases　of　cancer　tissue　samples　were　employed.　Results:　TMEM176A　was　methylated　in　53.66%　of　primary　lung　cancer.　Restoration　of　TMEM176A　expression　induced　cell　apoptosis　and　G2/M　phase　arrest,　and　inhibited　colony　formation,　cell　proliferation,　migration　and　invasion.　TMEM176A　suppressed　H1299　cell　xenograft　growth　in　mice.　Methylation　of　TMEM176A　activated　ERK　signaling　and　sensitized　H1299　and　H23　cells　to　AZD0156,　an　ATM　inhibitor.　Conclusion:　The　expression　of　TMEM176A　is　regulated　by　promoter　region　methylation.　Methylation　of　TMEM176A　is　a　potential　lung　cancer　diagnostic　marker　and　a　novel　synthetic　lethal　therapeutic　marker　for　AZD0156.