Abstract
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.
© 2011 Schatz et al.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Lymphoma / drug therapy
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Lymphoma / genetics
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Lymphoma / metabolism*
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Multiprotein Complexes
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Protein Biosynthesis*
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proteins / genetics
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Proteins / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
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Proto-Oncogene Proteins c-pim-1 / genetics
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Proto-Oncogene Proteins c-pim-1 / metabolism*
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RNA Caps / genetics
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RNA Caps / metabolism*
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Signal Transduction*
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Cells, Cultured
Substances
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Antibiotics, Antineoplastic
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Crtc1 protein, mouse
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Multiprotein Complexes
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PIM2 protein, human
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Pim2 protein, mouse
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Protein Kinase Inhibitors
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Proteins
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Proto-Oncogene Proteins
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RNA Caps
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Transcription Factors
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Mechanistic Target of Rapamycin Complex 1
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PIM1 protein, human
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Pim1 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-pim-1
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TOR Serine-Threonine Kinases
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Sirolimus