title: RAD001 enhances the potency of BEZ235 to inhibit mTOR signaling and tumor growth.
abstract: The mammalian target of rapamycin (mTOR) is regulated by oncogenic growth factor signals and plays a pivotal role in controlling cellular metabolism, growth and survival. Everolimus (RAD001) is an allosteric mTOR inhibitor that has shown marked efficacy in certain cancers but is unable to completely inhibit mTOR activity. ATP-competitive mTOR inhibitors such as NVP-BEZ235 can block rapamycin-insensitive mTOR readouts and have entered clinical development as anti-cancer agents. Here, we show the degree to which RAD001 and BEZ235 can be synergistically combined to inhibit mTOR pathway 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, the mTOR-4EBP1 pathway and tumorigenesis can be fully inhibited using lower doses of BEZ235. This is relevant since RAD001 is relatively well tolerated in patients while the toxicity profiles of ATP-competitive mTOR inhibitors are currently unknown.
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Beat
authors.initials: B
authors.lastname: Nyfeler
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.forename: Maria
authors.initials: M
authors.lastname: Pinzon-Ortiz
authors.forename: Zuncai
authors.initials: Z
authors.lastname: Wang
authors.forename: Anupama
authors.initials: A
authors.lastname: Reddy
authors.forename: Elina
authors.initials: E
authors.lastname: Pradhan
authors.forename: Rita
authors.initials: R
authors.lastname: Das
authors.forename: Joseph
authors.initials: J
authors.lastname: Lehár
authors.forename: Robert
authors.initials: R
authors.lastname: Schlegel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Finan
authors.forename: Z Alexander
authors.initials: ZA
authors.lastname: Cao
authors.forename: Leon O
authors.initials: LO
authors.lastname: Murphy
authors.forename: Alan
authors.initials: A
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004357:Drug Synergism; D000068338:Everolimus; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011804:Quinolines; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib; D020123:Sirolimus