PXD022329

PXD022329 is an original dataset announced via ProteomeXchange.

Title	Unbiased proteomic and phosphoproteomic analysis identifies response signatures and novel susceptibilities after combined MEK and mTOR inhibition in BRAFV600E mutant glioma
Description	The mitogen-activated protein kinase (MAPK) pathway is one of the most altered pathways in cancer. It is involved in the control of cell proliferation, invasion, metabolism, and resistance to therapy. A number of aggressive malignancies, including melanoma, colon cancer and glioma, are driven by an activating missense mutation (V600E) in one component of the pathway, BRAF. BRAF V600E mutated cancers may respond initially to MEK inhibition, but may develop resistance mediated by increased reliance on mTOR signaling. We have previously demonstrated that the combination of the MEK inhibitor trametinib with the dual mTORC1/2 inhibitor TAK228 improved survival and decreased vascularization in a BRAFV600E mutant glioma model. To elucidate the mechanism of action of, and the changes in response to, MEK and mTOR inhibition, we performed comprehensive unbiased proteomic and phosphoproteomic characterization of BRAFV600E mutant glioma xenografts after short-course treatment with trametinib and TAK228, alone and in combination. We identified distinct response signatures for each monotherapy and combination therapy and validated that combination treatment inhibited activation of the MAPK and mTOR pathways, increased apoptotic signaling and suppressed angiogenesis signaling. Furthermore, we found that trametinib and TAK228 combination treatment broadly suppressed the activity of the cyclin-dependent kinases and increased the levels of proteins (and their activating phosphorylations) involved in glycolysis, the TCA cycle, nucleotide biosynthesis and DNA replication. We also demonstrated activation of both receptor tyrosine kinase and histone deacetylase proteins. This study reports a detailed (phospho)proteomic analysis of the response of BRAFV600E mutant glioma to combined MEK and mTOR pathway inhibition and identifies a number of targetable upregulated proteins and pathways, providing new avenues for the development of additional rational combination therapies for aggressive BRAF-driven tumors.
HostingRepository	PRIDE
AnnounceDate	2021-07-30
AnnouncementXML	Submission_2021-07-29_21:53:55.680.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Micah Maxwell
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-11-04 01:37:51	ID requested
⏵ 1	2021-07-29 21:53:56	announced

Maxwell MJ, Arnold A, Sweeney H, Chen L, Lih TM, Schnaubelt M, Eberhart CG, Rubens JA, Zhang H, Clark DJ, Raabe EH, Mutant Glioma. Mol Cell Proteomics, 20():100123(2021) [pubmed]

submitter keyword: Glioma

BRAF V600E

Trametinib

TAK228

sapanisertib

INK128

MLN0128

Micah Joel Maxwell
contact affiliation	Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
contact email	mmaxwel1@jhmi.edu
lab head
Micah Maxwell
contact affiliation	The Johns Hopkins University School of Medicine, Division of Pediatric Oncology
contact email	mmaxwel1@jhmi.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD022329
     1. Label: PRIDE project
     2. Name: Unbiased proteomic and phosphoproteomic analysis identifies response signatures and novel susceptibilities after combined MEK and mTOR inhibition in BRAFV600E mutant glioma