PXD050650-1

PXD050650 is an original dataset announced via ProteomeXchange.

Title	Targeting cancer with small molecule pan-KRAS degraders
Description	Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue1. However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand2. Here we show that a single small molecule can be used to simultaneously and potently degrade 13 out of 17 of the most prevalent oncogenic KRAS alleles, including those not yet tractable by inhibitors. Compared with inhibition, degradation of oncogenic KRAS results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo. Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders. This is the proteomics analysis of ACBI3 and compoun 8, its negative control.
HostingRepository	PRIDE
AnnounceDate	2024-10-01
AnnouncementXML	Submission_2024-10-01_09:12:02.916.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Vesna Vetma
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Ascend

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-15 03:56:37	ID requested
⏵ 1	2024-10-01 09:12:03	announced

10.1126/SCIENCE.ADM8684;

submitter keyword: cancer,KRAS, PROTAC

Alessio Ciulli
contact affiliation	Centre For Targeted Protein Degradation (CeTPD) University of Dundee 1 Lindsay Place, DD1 5JJ Dundee, UK
contact email	a.ciulli@dundee.ac.uk
lab head
Vesna Vetma
contact affiliation	University of Dundee
contact email	v.vetma@dundee.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/2024/10/PXD050650

PRIDE project URI

• PRIDE
  1. PXD050650
     1. Label: PRIDE project
     2. Name: Targeting cancer with small molecule pan-KRAS degraders