title: Inhibition of 4EBP phosphorylation mediates the cytotoxic effect of mechanistic target of rapamycin kinase inhibitors in aggressive B-cell lymphomas.
abstract: Mechanistic target of rapamycin (mTOR) complex 1 is a central integrator of nutrient and growth factor inputs that controls cell growth in eukaryotes. The second generation of mTOR kinase inhibitors (TORKi), directly targeting the mTOR catalytic site, are more effective than rapamycin and its analogs in cancer treatment, particularly in inducing apoptosis. However, the mechanism underlying the cytotoxic effect of TORKi remains elusive. Herein, we demonstrate that TORKi-induced apoptosis is predominantly dependent on the loss of mTOR complex 1-mediated 4EBP activation. Knocking out RICTOR, a key component of mTOR complex 2, or inhibiting p70S6K has little effect on TORKi-induced apoptosis. Conversely, increasing the eIF4E:4EBP ratio by either overexpressing eIF4E or knocking out 4EBP1/2 protects lymphoma cells from TORKi-induced cytotoxicity. Furthermore, downregulation of MCL1 expression plays an important role in TORKi-induced apoptosis, whereas BCL-2 overexpression confers resistance to TORKi treatment. We further show that the therapeutic effect of TORKi in aggressive B-cell lymphomas can be predicted by BH3 profiling, and improved by combining it with pro-apoptotic drugs, especially BCL-2 inhibitors, bothin vitroandin vivoTaken together, the study herein provides mechanistic insight into TORKi cytotoxicity and identified a potential way to optimize its efficacy in the clinical treatment of aggressive B-cell lymphoma.
authors.affiliation: Departments of Pathology and Microbiology and Hematology Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Bi
authors.affiliation: Departments of Pathology and Microbiology and Hematology Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departments of Pathology and Microbiology and Hematology Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Lu
authors.affiliation: Departments of Pathology and Microbiology and Hematology Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departments of Pathology and Microbiology and Hematology Oncology, University of Nebraska Medical Center, Omaha, NE, USA.|The Sino-US Lymphoma Center, Tianjin Medical University Cancer Institute and Hospital, National Cancer Research Center, China.
authors.forename: Xianhuo
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Sino-US Lymphoma Center, Tianjin Medical University Cancer Institute and Hospital, National Cancer Research Center, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Meng
authors.affiliation: The Sino-US Lymphoma Center, Tianjin Medical University Cancer Institute and Hospital, National Cancer Research Center, China.
authors.forename: Huilai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: The Sino-US Lymphoma Center, Tianjin Medical University Cancer Institute and Hospital, National Cancer Research Center, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Departments of Pathology and Microbiology and Hematology Oncology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Vose
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: McKeithan
authors.affiliation: Departments of Pathology and Microbiology and Hematology Oncology, University of Nebraska Medical Center, Omaha, NE, USA kfu@unmc.edu.|The Sino-US Lymphoma Center, Tianjin Medical University Cancer Institute and Hospital, National Cancer Research Center, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064113:CRISPR-Cas Systems; D018450:Disease Progression; D000066630:Ectopic Gene Expression; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D018390:Gene Targeting / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012190:Retroviridae / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D000076225:Mechanistic Target of Rapamycin Complex 2; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases