Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies

• Published in: Blood Vol. 119; no. 2; pp. 476 - 487
• Main Authors: Gupta, Mamta, Hendrickson, Andrea E. Wahner, Yun, Seong Seok, Han, Jing Jing, Schneider, Paula A., Koh, Brian D., Stenson, Mary J., Wellik, Linda E., Shing, Jennifer C., Peterson, Kevin L., Flatten, Karen S., Hess, Allan D., Smith, B. Douglas, Karp, Judith E., Barr, Sharon, Witzig, Thomas E., Kaufmann, Scott H.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 12-01-2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Apoptosis - drug effects; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biological and medical sciences; Blotting, Western; Cell Proliferation - drug effects; Hematologic and hematopoietic diseases; Humans; Imidazoles - pharmacology; Immunoprecipitation; Immunosuppressive Agents - pharmacology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoid Neoplasia; Lymphoma - drug therapy; Lymphoma - metabolism; Lymphoma - pathology; Mechanistic Target of Rapamycin Complex 1; Medical sciences; Multiprotein Complexes; Phosphorylation - drug effects; Proteins - antagonists & inhibitors; Proteins - genetics; Proteins - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Real-Time Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Sirolimus - pharmacology; TOR Serine-Threonine Kinases; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Triazines - pharmacology; Tumor Cells, Cultured; p53 up-regulated modulator of apoptosis; Hematology; Cell death; Lymphoproliferative syndrome; Akt protein kinase; Hemopathy; Inhibitor; Apoptosis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-04-346601

The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and antiapoptotic signaling in lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are usually partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing divers lymphoid malignancies. In contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027–induced apoptosis depended on transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027–induced apoptosis in vitro. Moreover, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, up-regulated Puma, and induced regressions in Jeko xenografts. Collectively, these results not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo.