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PXD021877

PXD021877 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleQuantitative Tyr Phosphoproteomic Analyses of Tumor Adaptive Response to MAPK Inhibition
DescriptionAlthough targeted inhibition of the MAPK pathway has achieved remarkable patient responses in many cancers with MAPK hyperactivation, the development of resistance has remained a critical challenge. Besides genomic resistance mechanisms, adaptive tumor response also underlies the resistance to targeted MAPK inhibitors. It is being increasingly appreciated that such bypass mechanisms often lead to the activation of many pro-survival kinases, which complicates the rational design of combination therapies. Here we performed global tyrosine phosphoproteomic (pTyr) analyses and demonstrated that targeted inhibition of MAPK signaling in melanoma cells leads to a profound remodeling of the pTyr proteome. Intriguingly, many of these kinases contain a cholesterol binding motif, suggesting that altered cholesterol metabolism might drive, in a coordinated fashion, the activation of these kinases. Indeed, we found a dramatic accumulation of intracellular cholesterol in melanoma cells (with BRAFV600E mutations) and non-small cell lung cancer cells (with KRasG12C mutations) treated with MAPK and KrasG12C inhibitors, respectively. Importantly, depletion of cholesterol not only prevents the MAPK inhibition-induced feedback activation of pTyr singling but also enhances the cytotoxic effects of MAPK inhibitors, both in vitro and in vivo. Taken together, our findings provide the evidence suggesting that cholesterol functions as a master regulator of the tumor adaptive response to targeted MAPK inhibitors. These results also suggest that MAPK inhibitors could be combined with cholesterol-lowering agents to achieve a more complete and durable response in tumors with hyperactive MAPK signaling.
HostingRepositoryPRIDE
AnnounceDate2021-05-11
AnnouncementXMLSubmission_2021-05-11_08:28:22.666.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterXu-Dong Wang
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue
InstrumentLTQ Orbitrap Elite
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-10-07 07:32:36ID requested
12021-05-11 08:28:23announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Phosphoproteomic, Tumor Adaptive Response
Contact List
Yonghao Yu
contact affiliationDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA
contact emailyonghaoyu@utsouthwestern.edu
lab head
Xu-Dong Wang
contact affiliationUT Southwestern Medical Center
contact emailXu-Dong.Wang@utsouthwestern.edu
dataset submitter
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Dataset FTP location
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