PXD013075

PXD013075 is an original dataset announced via ProteomeXchange.

Title	KRASG12C inhibition produces a driver-limited state revealing collateral dependencies
Description	Inhibitors targeting KRASG12C are a promising new class of oncogene-specific therapeutics for the treatment of tumors driven by KRASG12C mutations. These molecules react with the mutant cysteine residue by binding covalently to the switch-II pocket present only in the inactive-GDP state of KRASG12C, sparing the wild type protein. We systematically probe genetic interactions with direct KRASG12C inhibition in cellular models of KRASG12C mutant lung and pancreatic cancer using a genome-scale CRISPR interference (CRISPRi) functional genomics platform. Our data reveal that repression of genes selectively essential in an oncogenic driverlimited cell state, which we term collateral dependencies (CDs), enhances cellular susceptibility to direct KRASG12C inhibition. We nominate two classes of combination therapies targeting CDs that increase KRASG12C target engagement or block residual survival pathways. We demonstrate in vitro and in vivo that both classes enhance response to anti-KRASG12C therapy and propose a new framework for assessing genetic dependencies with driver oncogenes.
HostingRepository	PRIDE
AnnounceDate	2020-03-23
AnnouncementXML	Submission_2020-03-22_23:13:42.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Danielle Swaney
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-03-13 03:46:15	ID requested
⏵ 1	2020-03-22 23:13:44	announced

Lou K, Steri V, Ge AY, Hwang YC, Yogodzinski CH, Shkedi AR, Choi ALM, Mitchell DC, Swaney DL, Hann B, Gordan JD, Shokat KM, Gilbert LA, inhibition produces a driver-limited state revealing collateral dependencies. Sci Signal, 12(583):(2019) [pubmed]

submitter keyword: KRAS, lung cancer, pancreatic cancer

John D. Gordan
contact affiliation	Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA Department of Medicine and Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94158, USA
contact email	john.gordan@ucsf.edu
lab head
Danielle Swaney
contact affiliation	UCSF
contact email	daniswan@gmail.com
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/2020/03/PXD013075

PRIDE project URI

• PRIDE
  1. PXD013075
     1. Label: PRIDE project
     2. Name: KRASG12C inhibition produces a driver-limited state revealing collateral dependencies