title: Systematic combination screening reveals synergism between rapamycin and sunitinib against human lung cancer.
abstract: Mammalian target of rapamycin (mTOR) acts as a hub integrating signals from nutrient availability and growth factors and plays central roles in regulating protein synthesis and cell growth, which has been validated as a promising target for cancer therapy. Rapamycin and its analogues have emerged as the first generation of mTOR inhibitors, but their efficacy is modest in clinical settings. Combinatorial use of rapamycin with other drugs is a promising strategy to improve its anticancer activity. Here we developed an unbiased systematic binary screening platform aiming to discover new remedy for rapamycin-based cancer therapy. We found that sunitinib emerged as one of the clinically available anticancer drugs screened that displayed significant synergy with rapamycin in NSCLC cells. Combination of rapamycin with sunitinib resulted in enhanced cell cycle arrest in G1 phase, which was accompanied with enhanced suppression of mTOR signaling and disruption of the negative feedback loop that activate AKT upon mTORC1 inhibition. Furthermore, sunitinib and rapamycin displayed synergistic activity against tube formation by human microvessel endothelial cells as well as outgrowth of endothelial tubes and microvessels both in vitro and in vivo, which is associated with down-regulation of VEGF secretion and HIF1α expression. Our study demonstrated that new combinatorial regimen could be identified via systematic drug combination screening and established a mechanistic rationale for a combination approach using rapalogs and sunitinib in the treatment of human NSCLC.
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
authors.forename: Xian
authors.initials: X
authors.lastname: Li
authors.forename: Lin-Jiang
authors.initials: LJ
authors.lastname: Tong
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Ling-Hua
authors.initials: LH
authors.lastname: Meng
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000188:drug therapy*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints; D015870:Gene Expression / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D046509:Tissue Culture Techniques; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib; D020123:Sirolimus
keywords: Combination; Non-small cell lung cancer; Rapamycin; Sunitinib