Genetic and pharmacologic evidence that mTOR targeting outweighs mTORC1 Inhibition as an antimyeloma strategy

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, proliferation, metabolism, and cell survival, and plays those roles by forming two functionally distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Deregulation of the mTOR pathway has been found in different cancers, including multiple myeloma. Agents acting on mTORC such as rapamycin and derivatives, are being explored as antitumoral strategies. However, whether targeting mTOR would be a more effective antimyeloma strategy than exclusively acting on the mTORC1 branch remains to be established. In this report, we explored the activation status of mTOR routes in malignant plasma cells, and analyzed the contribution of mTOR and its two signaling branches to the proliferation of myeloma cells. Gene expression profiling demonstrated deregulation ofmTORpathway-related genes inmyelomaplasmacells from patients. Activation of the mTOR pathway in myelomatous plasma cells was corroborated by flow cytometric analyses. RNA interference (RNAi) experiments indicated that mTORC1 predominated over mTORC2 in the control of myeloma cell proliferation. However, mTOR knockdown had a superior antiproliferative effect than acting only onmTORC1 ormTORC2. Pharmacologic studies corroborated that the neutralization ofmTORhas a stronger antimyeloma effect than the individual inhibition of mTORC1 or mTORC2. Together, our data support the clinical development of agents that widely target mTOR, instead of agents, such as rapamycin or its derivatives, that solely act on mTORC1.This work was supported by grants from the Ministry of Science and Education of Spain (BFU2006-01813/BMC and BFU2009-07728/BMC). X. Chen received research grant support from the Cancer Center Network Program from the Instituto de Salud Carlos III (RD06/0020/0041) and E. Diaz-Rodriguez from the Spanish Association for Cancer Research (AECC). Our Cancer Research Institute and the work carried out at our laboratory receive support from the European Community through the regional development funding program (FEDER), and from the Fundación Ramón Areces.Peer Reviewe