PXD052360

PXD052360 is an original dataset announced via ProteomeXchange.

Title	ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC
Description	Over 95% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic mutations in K-Ras. Upon treatment with K-Ras inhibitors, PDAC cancer cells undergo metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. However, direct inhibition of complex I is poorly tolerated in patients due to on-target induction of peripheral neuropathy. In this work, we develop molecular glue degraders against ZBTB11, a C2H2 zinc finger transcription factor that regulates the nuclear transcription of components of the mitoribosome and electron transport chain. Our ZBTB11 degraders leverage the differences in demand for biogenesis of mitochondrial components between human neurons and rapidly-dividing pancreatic cancer cells, to selectively target the K-Ras inhibitor resistant state in PDAC. Combination treatment of both K28 Ras inhibitor-resistant cell lines and multidrug resistant patient-derived organoids resulted in superior anti-cancer activity compared to single agent treatment, while sparing hiPSC-derived neurons. Proteomic and stable isotope tracing studies revealed mitoribosome depletion and impairment of the TCA cycle as key events that mediate this response. Together, this work validates ZBTB11 as a vulnerability in K-Ras inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.
HostingRepository	PRIDE
AnnounceDate	2025-07-15
AnnouncementXML	Submission_2025-07-14_20:45:12.103.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Min Ma
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro; LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-17 22:00:01	ID requested
⏵ 1	2025-07-14 20:45:12	announced

Dataset with its publication pending

submitter keyword: ZBTB11 PDAC K-Ras Metabolic hiPSC

Fleur Ferguson
contact affiliation	Department of Chemistry & Biochemistry Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego 9500 Gillman Drive, La Jolla, CA 92093
contact email	FLFERGUSON@ucsd.edu
lab head
Min Ma
contact affiliation	University of California San Diego
contact email	mim030@ucsd.edu
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/2025/07/PXD052360

PRIDE project URI

• PRIDE
  1. PXD052360
     1. Label: PRIDE project
     2. Name: ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC