PXD077254-1

PXD077254 is an original dataset announced via ProteomeXchange.

Title	Deep Proteomic and Phosphoproteomic Profiling in Proteasome Inhibitor-Resistant Multiple Myeloma
Description	Proteasome inhibitors (PIs) are frontline therapies for multiple myeloma (MM). Although MM patients initially respond to PIs, resistance frequently emerges. While clinical PIs primarily target the same proteasomal catalytic subunit (PSMB5), the extent to which resistance mechanisms are shared among different PIs remains poorly understood. To elucidate these resistance mechanisms, we performed deep proteomic and phosphoproteomic profiling of 12 MM cell line models, comprising four parental lineages (AMO-1, ARH77, L363, and RPMI8226) and their paired derivatives with acquired resistance to bortezomib (BTZ) and carfilzomib (CFZ). We quantified over 7,000 proteins and up to 10,000 phosphopeptides per cell line, enabling a systematic comparative analysis of shared and cell line-specific resistance signatures. Crucially, we discovered that acquired PI resistance is primarily driven by massive, stable reprogramming of the global proteome, while the phosphoproteome remains surprisingly constrained. Alongside known adaptations such as the overexpression of the PI target PSMB5 and the drug efflux transporter ABCB1, we identified the antioxidant flavoenzymes NQO1 and NQO2 as significantly upregulated proteins under chronic proteotoxic stress. Importantly, our functional validation revealed that protein abundance does not strictly dictate essentiality; even in contexts with lower basal expression, NQO2 serves as a critical vulnerability. Co-inhibiting NQO1 alongside the established ABCB1 efflux pump effectively restored PI sensitivity. Collectively, our dataset provides a rich resource for MM research and reveals pan-NQO inhibition as a highly effective, actionable strategy to overcome PI resistance.
HostingRepository	PRIDE
AnnounceDate	2026-07-15
AnnouncementXML	Submission_2026-07-15_03:13:37.095.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Chien-Yun Lee
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2026-04-16 10:20:23	ID requested
⏵ 1	2026-07-15 03:13:38	announced

Lee CY, Han S, Haertle L, Munawar U, Vogt C, Streubel J, Besse A, Besse L, Driessen C, Einsele H, Waldschmidt J, Kort, ü, m M, Kuster B, Proteome Profiling Reveals NQO2 Activity Contributing to Proteasome Inhibitor Resistance in Multiple Myeloma Cell Lines. Mol Cell Proteomics, 25(8):101615(2026) [pubmed]

10.1016/j.mcpro.2026.101615;

submitter keyword: Phosphoproteomics, Proteasome Inhibitor Resistance, Quantitative Proteomics,Multiple Myeloma

Bernhard Kuster
contact affiliation	Chair of Proteomics and Bioanalytics, School of Life Sciences, Technical University of Munich, Germany
contact email	kuster@tum.de
lab head
Chien-Yun Lee
contact affiliation	Chair of Proteomics and Bioanalytics, Technical University of Munich, Germany
contact email	chienyun.lee@tum.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/07/PXD077254

PRIDE project URI

• PRIDE
  1. PXD077254
     1. Label: PRIDE project
     2. Name: Deep Proteomic and Phosphoproteomic Profiling in Proteasome Inhibitor-Resistant Multiple Myeloma