title: Control of translational activation by PIM kinase in activated B-cell diffuse large B-cell lymphoma confers sensitivity to inhibition by PIM447.
abstract: The PIM family kinases promote growth and survival of tumor cells and are expressed in a wide variety of human cancers. Their potential as therapeutic targets, however, is complicated by overlapping activities with multiple other pathways and remains poorly defined in most clinical scenarios. Here we explore activity of the new pan-PIM inhibitor PIM447 in a variety of lymphoid-derived tumors. We find strong activity in cell lines derived from the activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL). Sensitive lines show lost activation of the mTORC1 signaling complex and subsequent lost activation of cap-dependent protein translation. In addition, we characterize recurrent PIM1 protein-coding mutations found in DLBCL clinical samples and find most preserve the wild-type protein's ability to protect cells from apoptosis but do not bypass activity of PIM447. Pan-PIM inhibition therefore may have an important role to play in the therapy of selected ABC-DLBCL cases.
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Peters
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, USA.
authors.forename: Ana A
authors.initials: AA
authors.lastname: Tula-Sanchez
authors.affiliation: Bio5 Institute, University of Arizona, Tucson, AZ, USA.
authors.forename: Praechompoo
authors.initials: P
authors.lastname: Pongtornpipat
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Schatz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
keywords: ABC-DLBCL; B-cell receptor signaling; PIM kinase; lymphomagenesis; cap-dependent translation