PXD043444

PXD043444 is an original dataset announced via ProteomeXchange.

Title	Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability
Description	Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free dNTPs. How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins are central regulators that coordinate nucleotide synthesis and ROS generation to drive the development of numerous human cancers. We herein performed a CRISPR-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven metabolic dependency. Mechanistically, MYC orchestrated the balance of two metabolic pathways that act in parallel, the NOX4-ROS pathway and the PLK1-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as the first-in-class degrader that potently and selectively depletes NUDT1 in vivo. Administration of LC-1-40 disrupted MYC-controlled metabolic homeostasis, resulting in excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:18:37.952.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	minhui ye
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-06-30 21:35:12	ID requested
1	2023-12-26 16:22:44	announced
⏵ 2	2024-10-22 06:18:38	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: MYC,PLK1,NUDT1,Cancer，PROTAC

Guoliang Qing
contact affiliation	Department of Urology,Zhongnan Hospital of Wuhan University,Wuhan 430071,China. Frontier Science Center for Immunology and Metabolism,Medical Research Institute,Wuhan University,Wuhan 430071,China.
contact email	qingguoliang@whu.eu.cn
lab head
minhui ye
contact affiliation	wuhan university
contact email	2017206500005@whu.edu.cn
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/2023/12/PXD043444

PRIDE project URI

• PRIDE
  1. PXD043444
     1. Label: PRIDE project
     2. Name: Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability