title: The combination of RAD001 and NVP-BEZ235 exerts synergistic anticancer activity against non-small cell lung cancer in vitro and in vivo.
abstract: The phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling axis has emerged as a novel target for cancer therapy. Agents that inhibit PI3K, mTOR or both are currently under development. The mTOR allosteric inhibitor, RAD001, and the PI3K/mTOR dual kinase inhibitor, BEZ235, are examples of these agents. We were interested in developing strategies to enhance mTOR-targeted caner therapy. In this study, we found that BEZ235 alone effectively inhibited the growth of rapamycin-resistant cancer cells. Interestingly, the combination of sub-optimal concentrations of RAD001 and BEZ235 exerted synergistic inhibition of the growth of human lung cancer cells along with induction of apoptosis and G1 arrest. Furthermore, the combination was also more effective than either agent alone in inhibiting the growth of lung cancer xenografts in mice. The combination showed enhanced effects on inhibiting mTOR signaling and reducing the expression of c-Myc and cyclin D1. Taken together, our results suggest that the combination of RAD001 and BEZ235 is a novel strategy for cancer therapy.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, United States of America.
authors.forename: Cheng-Xiong
authors.initials: CX
authors.lastname: Xu
authors.forename: Yikun
authors.initials: Y
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Yue
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D000068338:Everolimus; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D039562:Eukaryotic Initiation Factor-4F; D007093:Imidazoles; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; D019938:Cyclin D1; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib; D020123:Sirolimus