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

• Published in: Molecular cancer therapeutics 2014-02, Vol.13 (2), p.504-516
• Main Authors: Chen, Xi, Díaz-Rodríguez, Elena, Ocio, Enrique M, Paiva, Bruno, Mortensen, Deborah S, Lopez-Girona, Antonia, Chopra, Rajesh, Miguel, Jesús San, Pandiella, Atanasio
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - pharmacology; Apoptosis - drug effects; Blotting, Western; Cell Cycle Checkpoints - drug effects; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Coculture Techniques; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Imidazoles - pharmacology; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Pyrazines - pharmacology; RNA Interference; Signal Transduction - drug effects; Signal Transduction - genetics; Sirolimus - pharmacology; Stromal Cells - drug effects; Stromal Cells - metabolism; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumor Cells, Cultured
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-13-0022

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 mTORC1, 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 of mTOR pathway-related genes in myeloma plasma cells 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 on mTORC1 or mTORC2. Pharmacologic studies corroborated that the neutralization of mTOR has 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.