Glioblastoma　multiforme　(GBM)　is　a　fatal　disease　without　effective　therapy.　Identification　of　new　biomarkers　for　prognosis　would　enable　more　rational　selections　of　strategies　to　cure　patients　with　GBM　and　prevent　disease　relapse.Seven　datasets　derived　from　GBM　patients　using　microarray　or　next　generation　sequencing　in　R2　online　database　(http://r2.amc.nl)　were　extracted　and　then　analyzed　using　JMP　software.　The　survival　distribution　was　calculated　according　to　the　Kaplan-Meier　method　and　the　significance　was　determined　using　log-rank　statistics.　The　sensitivity　of　a　panel　of　GBM　cell　lines　in　response　to　temozolomide　(TMZ),　salinomycin,　celastrol,　and　triptolide　treatments　was　evaluated　using　MTS　and　tumor-sphere　formation　assay.We　identified　that　CD44,　ATP　binding　cassette　subfamily　C　member　3　(ABCC3),　and　tumor　necrosis　factor　receptor　subfamily　member　1A　(TNFRSF1A)　as　highly　expressed　genes　in　GBMs　are　associated　with　patients＇　poor　outcomes　and　therapy　resistance.　Furthermore,　these　three　markers　combined　with　MGMT,　a　conventional　GBM　marker,　can　classify　GBM　patients　into　five　new　subtypes　with　different　overall　survival　time　in　response　to　treatment.　The　four-gene　signature　and　the　therapy　response　of　GBMs　to　a　panel　of　therapeutic　compounds　were　confirmed　in　a　panel　of　GBM　cell　lines.The　data　indicate　that　the　four-gene　panel　can　be　used　as　a　therapy　response　index　for　GBM　patients　and　potential　therapeutic　targets.　These　results　provide　important　new　insights　into　the　early　diagnosis　and　the　prognosis　for　GBM　patients　and　introduce　potential　targets　for　GBM　therapeutics.　FUND:　Baylor　Scott　&　White　Health　Startup　Fund　(E.W.);　Collaborative　Faculty　Research　Investment　Program　(CFRIP)　of　Baylor　University,　Baylor　Scott　&　White　Health,　and　Baylor　College　of　Medicine　(E.W.,　T.S.,　J.H.H.);　NIH　R01　NS067435　(J.H.H.);　Scott　&　White　Plummer　Foundation　Grant　(J.H.H.);　National　Science　Foundation　in　China　816280007　(J.H.H.　and　Fu.W.).