PMID- 34298159
OWN - NLM
STAT- MEDLINE
DCOM- 20220324
LR  - 20240226
IS  - 1535-9484 (Electronic)
IS  - 1535-9476 (Print)
IS  - 1535-9476 (Linking)
VI  - 20
DP  - 2021
TI  - Unbiased Proteomic and Phosphoproteomic Analysis Identifies Response Signatures 
      and Novel Susceptibilities After Combined MEK and mTOR Inhibition in BRAF(V600E) 
      Mutant Glioma.
PG  - 100123
LID - S1535-9476(21)00095-5 [pii]
LID - 10.1016/j.mcpro.2021.100123 [doi]
LID - 100123
AB  - The mitogen-activated protein kinase pathway is one of the most frequently 
      altered pathways in cancer. It is involved in the control of cell proliferation, 
      invasion, and metabolism, and can cause resistance to therapy. A number of 
      aggressive malignancies, including melanoma, colon cancer, and glioma, are driven 
      by a constitutively activating missense mutation (V600E) in the v-Raf murine 
      sarcoma viral oncogene homolog B (BRAF) component of the pathway. 
      Mitogen-activated protein kinase kinase (MEK) inhibition is initially effective 
      in targeting these cancers, but reflexive activation of mammalian target of 
      rapamycin (mTOR) signaling contributes to frequent therapy resistance. We have 
      previously demonstrated that combination treatment with the MEK inhibitor 
      trametinib and the dual mammalian target of rapamycin complex 1/2 inhibitor 
      TAK228 improves survival and decreases vascularization in a BRAF(V600E) mutant 
      glioma model. To elucidate the mechanism of action of this combination therapy 
      and understand the ensuing tumor response, we performed comprehensive unbiased 
      proteomic and phosphoproteomic characterization of BRAF(V600E) mutant glioma 
      xenografts after short-course treatment with trametinib and TAK228. We identified 
      13,313 proteins and 30,928 localized phosphosites, of which 12,526 proteins and 
      17,444 phosphosites were quantified across all samples (data available via 
      ProteomeXchange; identifier PXD022329). We identified distinct response 
      signatures for each monotherapy and combination therapy and validated that 
      combination treatment inhibited activation of the mitogen-activated protein 
      kinase and mTOR pathways. Combination therapy also increased apoptotic signaling, 
      suppressed angiogenesis signaling, and broadly suppressed the activity of the 
      cyclin-dependent kinases. In response to combination therapy, both epidermal 
      growth factor receptor and class 1 histone deacetylase proteins were activated. 
      This study reports a detailed (phospho)proteomic analysis of the response of 
      BRAF(V600E) mutant glioma to combined MEK and mTOR pathway inhibition and 
      identifies new targets for the development of rational combination therapies for 
      BRAF-driven tumors.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Maxwell, Micah J
AU  - Maxwell MJ
AD  - Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, The 
      Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic 
      address: mmaxwel1@jhmi.edu.
FAU - Arnold, Antje
AU  - Arnold A
AD  - Division of Neuropathology, Department of Pathology, The Johns Hopkins University 
      School of Medicine, Baltimore, Maryland, USA.
FAU - Sweeney, Heather
AU  - Sweeney H
AD  - Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, The 
      Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
FAU - Chen, Lijun
AU  - Chen L
AD  - Department of Pathology, The Johns Hopkins University School of Medicine, 
      Baltimore, Maryland, USA.
FAU - Lih, Tung-Shing M
AU  - Lih TM
AD  - Department of Pathology, The Johns Hopkins University School of Medicine, 
      Baltimore, Maryland, USA.
FAU - Schnaubelt, Michael
AU  - Schnaubelt M
AD  - Department of Pathology, The Johns Hopkins University School of Medicine, 
      Baltimore, Maryland, USA.
FAU - Eberhart, Charles G
AU  - Eberhart CG
AD  - Division of Neuropathology, Department of Pathology, The Johns Hopkins University 
      School of Medicine, Baltimore, Maryland, USA.
FAU - Rubens, Jeffrey A
AU  - Rubens JA
AD  - Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, The 
      Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
FAU - Zhang, Hui
AU  - Zhang H
AD  - Department of Pathology, The Johns Hopkins University School of Medicine, 
      Baltimore, Maryland, USA.
FAU - Clark, David J
AU  - Clark DJ
AD  - Department of Pathology, The Johns Hopkins University School of Medicine, 
      Baltimore, Maryland, USA.
FAU - Raabe, Eric H
AU  - Raabe EH
AD  - Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, The 
      Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Division 
      of Neuropathology, Department of Pathology, The Johns Hopkins University School 
      of Medicine, Baltimore, Maryland, USA. Electronic address: eraabe2@jhmi.edu.
LA  - eng
GR  - L40 CA242540/CA/NCI NIH HHS/United States
GR  - P30 CA006973/CA/NCI NIH HHS/United States
GR  - U24 CA210985/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210721
PL  - United States
TA  - Mol Cell Proteomics
JT  - Molecular & cellular proteomics : MCP
JID - 101125647
RN  - 0 (Benzoxazoles)
RN  - 0 (Phosphoproteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridones)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrimidinones)
RN  - 33E86K87QN (trametinib)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - JGH0DF1U03 (sapanisertib)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use
MH  - Benzoxazoles/pharmacology/*therapeutic use
MH  - Brain Neoplasms/*drug therapy/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Female
MH  - Glioma/*drug therapy/genetics/metabolism
MH  - Humans
MH  - Mice, Nude
MH  - Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors
MH  - Phosphoproteins/*metabolism
MH  - Protein Kinase Inhibitors/pharmacology/*therapeutic use
MH  - Proteomics
MH  - Proto-Oncogene Proteins B-raf/genetics
MH  - Pyridones/pharmacology/*therapeutic use
MH  - Pyrimidines/pharmacology/*therapeutic use
MH  - Pyrimidinones/pharmacology/*therapeutic use
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Mice
PMC - PMC8363840
OTO - NOTNLM
OT  - TAK228
OT  - angiogenesis
OT  - apoptosis
OT  - drug targets
OT  - glioma
OT  - mouse models
OT  - phosphoproteome
OT  - sapanisertib
OT  - signal transduction
OT  - tandem MS
OT  - trametinib
COIS- Conflict of interest The authors declare no competing interests.
EDAT- 2021/07/24 06:00
MHDA- 2022/03/25 06:00
PMCR- 2021/07/21
CRDT- 2021/07/23 20:14
PHST- 2021/04/30 00:00 [received]
PHST- 2021/07/01 00:00 [revised]
PHST- 2021/07/16 00:00 [accepted]
PHST- 2021/07/24 06:00 [pubmed]
PHST- 2022/03/25 06:00 [medline]
PHST- 2021/07/23 20:14 [entrez]
PHST- 2021/07/21 00:00 [pmc-release]
AID - S1535-9476(21)00095-5 [pii]
AID - 100123 [pii]
AID - 10.1016/j.mcpro.2021.100123 [doi]
PST - ppublish
SO  - Mol Cell Proteomics. 2021;20:100123. doi: 10.1016/j.mcpro.2021.100123. Epub 2021 
      Jul 21.