title: Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies.
abstract: Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K δ isoform inhibitor TGR-1202, but not the approved PI3Kδ inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells. TGR-1202 and carfilzomib (TC) synergistically inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), leading to suppression of c-Myc translation and silencing of c-Myc-dependent transcription. The synergistic cytotoxicity of TC was rescued by overexpression of eIF4E or c-Myc. TGR-1202, but not other PI3Kδ inhibitors, inhibited casein kinase-1 ε (CK1ε). Targeting CK1ε using a selective chemical inhibitor or short hairpin RNA complements the effects of idelalisib, as a single agent or in combination with carfilzomib, in repressing phosphorylation of 4E-BP1 and the protein level of c-Myc. These results suggest that TGR-1202 is a dual PI3Kδ/CK1ε inhibitor, which may in part explain the clinical activity of TGR-1202 in aggressive lymphoma not found with idelalisib. Targeting CK1ε should become an integral part of therapeutic strategies targeting translation of oncogenes such as c-Myc.
authors: Center for Lymphoid Malignancies.|Division of Experimental Therapeutics.|Division of Hematology and Oncology, Department of Medicine.
authors: Changchun
authors: 0000-0001-9372-6086
authors: C
authors: Deng
authors: Division of Experimental Therapeutics.
authors: Mark R
authors: MR
authors: Lipstein
authors: Division of Experimental Therapeutics.
authors: Luigi
authors: L
authors: Scotto
authors: Division of Experimental Therapeutics.
authors: Xavier O
authors: XO
authors: Jirau Serrano
authors: Division of Experimental Therapeutics.
authors: Michael A
authors: MA
authors: Mangone
authors: Division of Hematology and Oncology, Department of Medicine.
authors: Shirong
authors: S
authors: Li
authors: Department of Systems Biology, Howard Hughes Medical Institute.
authors: Jeremie
authors: J
authors: Vendome
authors: Department of Biomedical Informatics, and.
authors: Yun
authors: Y
authors: Hao
authors: Division of Experimental Therapeutics.
authors: Xiaoming
authors: X
authors: Xu
authors: Division of Experimental Therapeutics.
authors: Shi-Xian
authors: SX
authors: Deng
authors: Joint Centers for Systems Biology-Columbia Genome Center, Columbia University Medical Center, New York, NY; and.
authors: Ronald B
authors: RB
authors: Realubit
authors: Department of Biomedical Informatics, and.
authors: Nicholas P
authors: NP
authors: Tatonetti
authors: Joint Centers for Systems Biology-Columbia Genome Center, Columbia University Medical Center, New York, NY; and.
authors: Charles
authors: C
authors: Karan
authors: Division of Hematology and Oncology, Department of Medicine.
authors: Suzanne
authors: S
authors: Lentzsch
authors: Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA.
authors: David A
authors: DA
authors: Fruman
authors: Department of Systems Biology, Howard Hughes Medical Institute.
authors: Barry
authors: B
authors: Honig
authors: Division of Experimental Therapeutics.
authors: Donald W
authors: DW
authors: Landry
authors: Center for Lymphoid Malignancies.|Division of Experimental Therapeutics.
authors: Owen A
authors: OA
authors: O'Connor
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D019337:Hematologic Neoplasms; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C524865:carfilzomib; D048149:Casein Kinase 1 epsilon