PMID- 27784673
OWN - NLM
STAT- MEDLINE
DCOM- 20170814
LR  - 20220311
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 129
IP  - 1
DP  - 2017 Jan 5
TI  - Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kdelta and 
      CK1epsilon in hematological malignancies.
PG  - 88-99
LID - 10.1182/blood-2016-08-731240 [doi]
AB  - 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 delta isoform inhibitor TGR-1202, 
      but not the approved PI3Kdelta 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 PI3Kdelta inhibitors, inhibited casein kinase-1 epsilon (CK1epsilon). 
      Targeting CK1epsilon 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 PI3Kdelta/CK1epsilon inhibitor, which 
      may in part explain the clinical activity of TGR-1202 in aggressive lymphoma not 
      found with idelalisib. Targeting CK1epsilon should become an integral part of 
      therapeutic strategies targeting translation of oncogenes such as c-Myc.
CI  - (c) 2017 by The American Society of Hematology.
FAU - Deng, Changchun
AU  - Deng C
AUID- ORCID: 0000-0001-9372-6086
AD  - Center for Lymphoid Malignancies.
AD  - Division of Experimental Therapeutics.
AD  - Division of Hematology and Oncology, Department of Medicine.
FAU - Lipstein, Mark R
AU  - Lipstein MR
AD  - Division of Experimental Therapeutics.
FAU - Scotto, Luigi
AU  - Scotto L
AD  - Division of Experimental Therapeutics.
FAU - Jirau Serrano, Xavier O
AU  - Jirau Serrano XO
AD  - Division of Experimental Therapeutics.
FAU - Mangone, Michael A
AU  - Mangone MA
AD  - Division of Experimental Therapeutics.
FAU - Li, Shirong
AU  - Li S
AD  - Division of Hematology and Oncology, Department of Medicine.
FAU - Vendome, Jeremie
AU  - Vendome J
AD  - Department of Systems Biology, Howard Hughes Medical Institute.
FAU - Hao, Yun
AU  - Hao Y
AD  - Department of Biomedical Informatics, and.
FAU - Xu, Xiaoming
AU  - Xu X
AD  - Division of Experimental Therapeutics.
FAU - Deng, Shi-Xian
AU  - Deng SX
AD  - Division of Experimental Therapeutics.
FAU - Realubit, Ronald B
AU  - Realubit RB
AD  - Joint Centers for Systems Biology-Columbia Genome Center, Columbia University 
      Medical Center, New York, NY; and.
FAU - Tatonetti, Nicholas P
AU  - Tatonetti NP
AD  - Department of Biomedical Informatics, and.
FAU - Karan, Charles
AU  - Karan C
AD  - Joint Centers for Systems Biology-Columbia Genome Center, Columbia University 
      Medical Center, New York, NY; and.
FAU - Lentzsch, Suzanne
AU  - Lentzsch S
AD  - Division of Hematology and Oncology, Department of Medicine.
FAU - Fruman, David A
AU  - Fruman DA
AD  - Department of Molecular Biology and Biochemistry, University of California 
      Irvine, Irvine, CA.
FAU - Honig, Barry
AU  - Honig B
AD  - Department of Systems Biology, Howard Hughes Medical Institute.
FAU - Landry, Donald W
AU  - Landry DW
AD  - Division of Experimental Therapeutics.
FAU - O'Connor, Owen A
AU  - O'Connor OA
AD  - Center for Lymphoid Malignancies.
AD  - Division of Experimental Therapeutics.
LA  - eng
GR  - R01 GM107145/GM/NIGMS NIH HHS/United States
GR  - S10 OD018121/OD/NIH HHS/United States
GR  - S10 OD020056/OD/NIH HHS/United States
GR  - S10 RR027050/RR/NCRR NIH HHS/United States
PT  - Journal Article
DEP - 20161026
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Oligopeptides)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 72X6E3J5AR (carfilzomib)
RN  - EC 2.7.11.1 (Casein Kinase 1 epsilon)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Casein Kinase 1 epsilon/*antagonists & inhibitors
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - *Hematologic Neoplasms
MH  - Humans
MH  - Mice
MH  - Oligopeptides/pharmacology
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Biosynthesis
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-myc/*biosynthesis
MH  - Random Allocation
MH  - Xenograft Model Antitumor Assays
PMC - PMC5216267
EDAT- 2016/10/28 06:00
MHDA- 2017/08/15 06:00
PMCR- 2017/01/05
CRDT- 2016/10/28 06:00
PHST- 2016/08/02 00:00 [received]
PHST- 2016/10/12 00:00 [accepted]
PHST- 2016/10/28 06:00 [pubmed]
PHST- 2017/08/15 06:00 [medline]
PHST- 2016/10/28 06:00 [entrez]
PHST- 2017/01/05 00:00 [pmc-release]
AID - S0006-4971(20)33829-5 [pii]
AID - 2016/731240 [pii]
AID - 10.1182/blood-2016-08-731240 [doi]
PST - ppublish
SO  - Blood. 2017 Jan 5;129(1):88-99. doi: 10.1182/blood-2016-08-731240. Epub 2016 Oct 
      26.