mk-2206 and Lymphoma--B-Cell

Topics: Allografts; Animals; B-Lymphocytes; Epstein-Barr Virus Infections; Female; Graft Rejection; Graft Survival; Heart Transplantation; Heterocyclic Compounds, 3-Ring; Humans; Inhibitory Concentration 50; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation; Organ Transplantation; Phosphoinositide-3 Kinase Inhibitors; Postoperative Complications; Proto-Oncogene Proteins c-akt; Purines; Quinazolinones; Sirolimus; TOR Serine-Threonine Kinases

The dysregulation of PI3K/AKT/mTORC1 signalling and/or hyperactivation of MYC are observed in a high proportion of human cancers, and together they form a 'super signalling' network mediating malignancy. A fundamental downstream action of this signalling network is up-regulation of ribosome biogenesis and subsequent alterations in the patterns of translation and increased protein synthesis, which are thought to be critical for AKT/MYC-driven oncogenesis. We have demonstrated that AKT and MYC cooperate to drive ribosomal DNA (rDNA) transcription and ribosome biogenesis, with AKT being essential for rDNA transcription and in vitro survival of lymphoma cells isolated from a MYC-driven model of B-cell lymphoma (Eμ-Myc) [Chan JC et al., (2011) Science Signalling 4, ra56]. Here we show that the allosteric AKT inhibitor MK-2206 rapidly and potently antagonizes rDNA transcription in Eμ-Myc B-cell lymphomas in vivo, and this is associated with a rapid reduction in indicators of disease burden, including spleen weight and the abundance of tumour cells in both the circulation and lymph nodes. Extended treatment of tumour-bearing mice with MK-2206 resulted in a significant delay in disease progression, associated with increased B-cell lymphoma apoptosis. Our findings suggest that malignant diseases characterized by unrestrained ribosome biogenesis may be vulnerable to therapeutic strategies that target the PI3K/AKT/mTORC1/MYC growth control network.

Topics: Animals; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Disease Progression; Dromaiidae; Heterocyclic Compounds, 3-Ring; Humans; Lymphoma, B-Cell; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Ribosomal; Signal Transduction; Transcription, Genetic