PXD021877 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Quantitative Tyr Phosphoproteomic Analyses of Tumor Adaptive Response to MAPK Inhibition |
Description | Although 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. |
HostingRepository | PRIDE |
AnnounceDate | 2021-05-11 |
AnnouncementXML | Submission_2021-05-11_08:28:22.666.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Xu-Dong Wang |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | phosphorylated residue |
Instrument | LTQ Orbitrap Elite |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2020-10-07 07:32:36 | ID requested | |
⏵ 1 | 2021-05-11 08:28:23 | announced | |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: Phosphoproteomic, Tumor Adaptive Response |
Contact List
Yonghao Yu |
contact affiliation | Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA |
contact email | yonghaoyu@utsouthwestern.edu |
lab head | |
Xu-Dong Wang |
contact affiliation | UT Southwestern Medical Center |
contact email | Xu-Dong.Wang@utsouthwestern.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD021877
- Label: PRIDE project
- Name: Quantitative Tyr Phosphoproteomic Analyses of Tumor Adaptive Response to MAPK Inhibition