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

Cancer Biology and Genetics Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 08/2011; 208(9):1799-807. DOI: 10.1084/jem.20110846
Source: PubMed


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.

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Available from: Neal Rosen, Mar 10, 2014
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    • "Mammalian expression constructs that were generated are described in detail in figures and in Supporting Information. SypHluorin was kindly provided by Yongling Zhu (Salk Institute) (Zhu and Stevens, 2008), and 4E-BP1–4Ala carrying alanine substitutions at four phosphorylation sites (Thr37, Thr46, Ser65, and Thr70), by Dr. Hans G. Wendel (Memorial Sloan-Kettering Cancer Center) (Schatz et al., 2011). "
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