RAD001 enhances the potency of BEZ235 to inhibit mTOR signaling and tumor growth
Tools
Tools
Nyfeler, Beat, Chen, Yan, Li, Xiaoyan, Pinzon-Ortiz, Maria, Wang, Zuncai, Reddy, Anupama, Pradhan, Elina, Das, Rita, Lehar, Joseph, Schlegel, Robert, Finan, Peter, Cao, Alex, Murphy, Leon and Huang, Alan (2012) RAD001 enhances the potency of BEZ235 to inhibit mTOR signaling and tumor growth. PLOS ONE, 7 (11). e48548-e48548. ISSN 1932-6203
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 that RAD001 and BEZ235 can be synergistically combined to inhibit mTOR pathway activation, cell proliferation and tumor growth in vivo. RAD001 and BEZ235 synergized in several cancer lines representing different lineages and genetic backgrounds. Critically, in the presence of RAD001, less BEZ235 is needed to fully inhibit the mTOR-4EBP1 pathway and tumorigenesis. This suggests that tumors can be targeted with lower doses of ATP-competitive mTOR inhibitors when combined with RAD001. This is relevant since RAD001 is relatively well tolerated in patients while the toxicity profiles of ATP-competitive mTOR inhibitors are currently unknown.
| Item Type: | Article |
|---|---|
| Related URLs: | |
| Additional Information: | This is a revised version of OAK ID #6374. |
| Related URLs: | |
| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/8143 |