RAD001 Enhances the Potency of BEZ235 to Inhibit mTOR Signaling and Tumor Growth 英文参考文献.docVIP

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RAD001 Enhances the Potency of BEZ235 to Inhibit mTOR Signaling and Tumor Growth 英文参考文献.doc

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RAD001 Enhances the Potency of BEZ235 to Inhibit mTOR Signaling and Tumor Growth 英文参考文献

RAD001EnhancesthePotencyofBEZ235toInhibit mTORSignalingandTumorGrowth BeatNyfeler1,YanChen2,XiaoyanLi2,MariaPinzon-Ortiz2,ZuncaiWang1,AnupamaReddy2, ElinaPradhan2,RitaDas2,JosephLeha′r2,RobertSchlegel2,PeterM.Finan1,Z.AlexanderCao2, LeonO.Murphy1,AlanHuang2* 1Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America, 2Oncology Translational Medicine,NovartisInstitutesforBioMedicalResearch,Cambridge,Massachusetts,UnitedStatesofAmerica Abstract The mammalian targetof rapamycin (mTOR)is regulated by oncogenicgrowth factor signals and playsapivotal role in controllingcellularmetabolism,growthandsurvival.Everolimus(RAD001)isanallostericmTORinhibitorthathasshown markedefficacyincertaincancersbutisunabletocompletelyinhibitmTORactivity.ATP-competitivemTORinhibitorssuch as NVP-BEZ235 can block rapamycin-insensitive mTOR readouts and have entered clinical development as anti-cancer agents.Here,weshowthedegreetowhichRAD001andBEZ235canbesynergisticallycombinedtoinhibitmTORpathway activation, cell proliferation and tumor growth, both in vitro and in vivo. RAD001 and BEZ235 synergized in cancer lines representing different lineages and genetic backgrounds. Strong synergy is seen in neuronal, renal, breast, lung, and haematopoietic cancer cells harboring abnormalities in PTEN, VHL, LKB1, Her2, or KRAS. Critically, in the presence of RAD001,themTOR-4EBP1pathwayandtumorigenesiscanbefullyinhibitedusinglowerdosesofBEZ235.Thisisrelevant since RAD001 is relatively well tolerated in patients while the toxicity profiles of ATP-competitive mTOR inhibitors are currentlyunknown. Citation: Nyfeler B, Chen Y, Li X, Pinzon-Ortiz M, Wang Z, et al. (2012) RAD001 Enhances the Potency of BEZ235 to Inhibit mTOR Signaling and Tumor Growth.PLoSONE7(11):e48548.doi:10.1371/journal.pone.0048548 Editor:YiqunG.Shellman,UniversityofColoradoSchoolofMedicine,UnitedStatesofAmerica ReceivedMarch27,2012;AcceptedSeptember26,2012;Publish