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.
Highlights
The mammalian target of rapamycin is a key regulator of cell growth, proliferation and cellular metabolism, and is activated downstream of several oncogenes and tumor suppressors
We show that the synergistic combination of RAD001 and BEZ235 is not restricted to these two tumor types, but rather inhibits mammalian target of rapamycin (mTOR) signaling, cell viability and tumorigenesis broadly in several different cancer lines, representing various lineages and genetic backgrounds
We chose the PTEN null glioblastoma U-87 MG cell line as a first model to explore the combination of RAD001 and BEZ235, and monitored mTOR pathway inhibition by western blot analysis
Summary
The mammalian target of rapamycin (mTOR) is a key regulator of cell growth, proliferation and cellular metabolism, and is activated downstream of several oncogenes and tumor suppressors. MTOR functions as part of at least two multi-protein complexes, mTORC1 and mTORC2. Amplification and activating mutations in PIK3CA, deletions and loss of function mutations in PTEN, LKB1 or TSC2 can all constitutively activate mTOR and its downstream signaling events [1,2]. Both of these complexes have been shown to have important roles in tumorigenesis [3,4]. Two main classes of mTOR inhibitors have been developed: allosteric inhibitors, typified by rapamycin and its derivatives (rapalogues); and ATP-competitive mTOR inhibitors [6,7,8]
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