PXD071906

PXD071906 is an original dataset announced via ProteomeXchange.

Title	Molidustat Targets a Synthetic Lethal Vulnerability in APC-Mutant Colorectal Cancer through GSTP1 and PHD2 Co-Inhibition
Description	APC mutations drive colorectal cancer (CRC) and create dependencies on metabolic and stress-adaptation pathways. To investigate vulnerabilities associated with hydroxylase inhibition in APC-mutant cells, we profiled the proteomic consequences of the clinical PHD2 inhibitor Molidustat using thermal proteome profiling and chemical proteomics. These analyses revealed GSTP1 as an unexpected off-target interactor whose enzymatic activity is directly inhibited by Molidustat. Quantitative proteomics of CRISPR knockout models showed that loss of GSTP1 and PHD2 individually induces partially overlapping stress responses, whereas combined loss produces a synergistic redox-collapse phenotype, characterised by oxidative stress, apoptotic signalling, and impaired proliferation, closely recapitulating the cellular response to Molidustat. Metabolomics confirmed elevated oxidative pressure and altered redox balance in the double knockout. In parallel, Molidustat selectively reduced viability in APC- and KRAS-mutant colonic organoids, an effect not reproduced by other hydroxylase inhibitors. Together, these data identify a GSTP1–PHD2 synthetic lethal interaction and demonstrate that Molidustat exploits this vulnerability, providing a mechanistic basis for its selective activity in APC-mutant CRC.
HostingRepository	PRIDE
AnnounceDate	2026-05-04
AnnouncementXML	Submission_2026-05-04_05:09:05.186.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Agata Makar
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-12 02:27:27	ID requested
⏵ 1	2026-05-04 05:09:06	announced

10.7554/ELIFE.110991.1;

submitter keyword: pulldown, expression proteomics,LC-MSMS

Alex von Kriegsheim
contact affiliation	Cancer Research UK Scotland Centre Institute of Genetics and Cancer University of Edinburgh
contact email	Alex.VonKriegsheim@ed.ac.uk
lab head
Agata Makar
contact affiliation	University of Edinburgh
contact email	amakar2@ed.ac.uk
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/2026/05/PXD071906

PRIDE project URI

• PRIDE
  1. PXD071906
     1. Label: PRIDE project
     2. Name: Molidustat Targets a Synthetic Lethal Vulnerability in APC-Mutant Colorectal Cancer through GSTP1 and PHD2 Co-Inhibition