title: Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.
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.
authors.affiliation: Cancer Biology and Genetics Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Schatz
authors.forename: Elisa
authors.initials: E
authors.lastname: Oricchio
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Wolfe
authors.forename: Man
authors.initials: M
authors.lastname: Jiang
authors.forename: Irina
authors.initials: I
authors.lastname: Linkov
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Maragulia
authors.forename: Weiji
authors.initials: W
authors.lastname: Shi
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Vinagolu K
authors.initials: VK
authors.lastname: Rajasekhar
authors.forename: Nen C
authors.initials: NC
authors.lastname: Pagano
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Zelenetz
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.forename: Hans-Guido
authors.initials: HG
authors.lastname: Wendel
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; C519509:Crtc1 protein, mouse; D046912:Multiprotein Complexes; C490587:PIM2 protein, human; C094167:Pim2 protein, mouse; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012315:RNA Caps; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus