Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma
Open Access
- 22 August 2011
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 208 (9), 1799-1807
- https://doi.org/10.1084/jem.20110846
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.Keywords
This publication has 36 references indexed in Scilit:
- Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemiaNature, 2010
- An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1Journal of Biological Chemistry, 2009
- Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological TargetsCell, 2009
- Tumorigenic activity and therapeutic inhibition of Rheb GTPaseGenes & Development, 2008
- mTORC1 promotes survival through translational control of Mcl-1Proceedings of the National Academy of Sciences, 2008
- Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma modelJCI Insight, 2008
- Dissecting eIF4E action in tumorigenesisGenes & Development, 2007
- Reverse engineering of regulatory networks in human B cellsNature Genetics, 2005
- Distinct types of diffuse large B-cell lymphoma identified by gene expression profilingNature, 2000
- The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic miceNature, 1985