Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma

• DOI: 10.1084/jem.20110846
• Publication Date: 2011-08-23T00:20:03Z
• Authors: Jonathan H. Schatz; Elisa Oricchio; Andrew L. Wolfe; Man Jiang; Irina Linkov; Jocelyn Maragulia; Weiji Shi; Zhigang Zhang; Vinagolu K. Rajas...; Nen C. Pagano; John A. Porco; Julie Teruya-Feld...; Neal Rosen; Andrew D. Zelenetz; Jerry Pelletier; Hans-Guido Wendel
• Keywords: 0301 basic medicine; Lymphoma; enzymologic; Signal transduction; Hodgkins lymphoma; Mice; Antibiotics; Transgenic mice; Cancer; Gene expression regulation; Leukemia; Antibiotics, Antineoplastic; 3. Good health; Gene Expression Regulation, Neoplastic; Medicine; Proto-oncogene proteins; research & experimental; Signal Transduction; RNA Caps; Mechanistic target of rapamycin complex 1; Protein-serine-threonine kinases; Multiprotein complexes; antineoplastic; Immunology; Research & experimental medicine; Protein kinase inhibitors; 610; Mechanistic Target of Rapamycin Complex 1; Protein Serine-Threonine Kinases; Tumor cells; Gene Expression Regulation, Enzymologic; 03 medical and health sciences; Proto-Oncogene Proteins c-pim-1; Proto-Oncogene Proteins; EIF4E; Transcription factors; Animals; Humans; cultured; Protein Kinase Inhibitors; Sirolimus; Brief Definitive Report; Proto-pncogene proteins c-pim-1; Proteins; Proto-oncogene proteins c-akt; Protein biosynthesis; Life sciences & biomedicine; B cell lymphoma; neoplastic; TOR serine-threonine kinases; Drug Resistance, Neoplasm; Drug resistance; Multiprotein Complexes; Protein Biosynthesis; Tumorigenesis; RNA caps; Proto-Oncogene Proteins c-akt; neoplasm

New anticancer drugs that target oncogenic signaling molecules have greatly improved the treatment of certain cancers. However, resistance to targeted therapeutics is a major clinical problem and the redundancy of oncogenic signaling pathways provides back-up mechanisms that allow cancer cells to escape. For example, the AKT and PIM kinases produce parallel oncogenic signals and share many molecular targets, including activators of cap-dependent translation. Here, we show that PIM kinase expression can affect the clinical outcome of lymphoma chemotherapy. We observe the same in animal lymphoma models. Whereas chemoresistance caused by AKT is readily reversed with rapamycin, PIM-mediated resistance is refractory to mTORC1 inhibition. However, both PIM- and AKT-expressing lymphomas depend on cap-dependent translation, and genetic or pharmacological blockade of the translation initiation complex is highly effective against these tumors. The therapeutic effect of blocking cap-dependent translation is mediated, at least in part, by decreased production of short-lived oncoproteins including c-MYC, Cyclin D1, MCL1, and the PIM1/2 kinases themselves. Hence, targeting the convergence of oncogenic survival signals on translation initiation is an effective alternative to combinations of kinase inhibitors.