PXD052325-1

PXD052325 is an original dataset announced via ProteomeXchange.

Title	Single-cell signaling analysis reveals that Major Vault Protein facilitates RasG12C inhibitor resistance
Description	Recently developed covalent inhibitors for RasG12C provide the first pharmacological tools to target mutant Ras-driven cancers. However, the rapid development of resistance to current clinical Ras G12C inhibitors is common. Presumably, a subpopulation of RasG12C-expressing cells adapt their signaling to evade these inhibitors and the mechanisms for this phenomenon are unclear due to the lack of tools that can measure signaling with single-cell resolution. Here, we utilized recently developed Ras sensors to profile the environment of active Ras and to measure the activity of endogenous Ras in order to pair structure (Ras signalosome) to function (Ras activity), respectively, at a single-cell level. With this approach, we identified a subpopulation of KRasG12C cells treated with RasG12C-GDP inhibitors underwent oncogenic signaling and metabolic changes driven by WT Ras at the golgi and mutant Ras at the mitochondria, respectively. Our Ras sensors identified Major Vault Protein (MVP) as a mediator of Ras activation at both compartments by scaffolding Ras signaling pathway components and metabolite channels. We found that recently developed RasG12C-GTP inhibitors also led to MVP-mediated WT Ras signaling at the golgi, demonstrating that this a general mechanism RasG12C inhibitor resistance. Overall, single-cell analysis of structure-function relationships enabled the discovery of a RasG12C inhibitor-resistant subpopulation driven by MVP, providing insight into the complex and heterogenous rewiring occurring during drug resistance in cancer.
HostingRepository	MassIVE
AnnounceDate	2024-05-17
AnnouncementXML	Submission_2024-05-17_11:06:45.001.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shao-En Ong
SpeciesList	scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-16 16:01:21	ID requested
⏵ 1	2024-05-17 11:06:45	announced

no publication

submitter keyword: Ras, signaling

Jason Z Zhang
contact affiliation	University of Washington
contact email	jzz0428@uw.edu
lab head
Dustin J Maly
contact affiliation	University of Washington
contact email	djmaly@uw.edu
lab head
Shao-En Ong
contact affiliation	University of Washington
contact email	shaoen@uw.edu
dataset submitter

MassIVE dataset URI

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