PXD014198-1

PXD014198 is an original dataset announced via ProteomeXchange.

Title	Genome-wide CRISPR screening reveals genetic modifiers of mutant EGFR dependence in NSCLC
Description	Human non-small-cell lung cancers (NSCLCs) harboring activating mutations in epidermal growth factor receptor (EGFR) frequently respond to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib. However, the responses are not durable, and the magnitude of tumor regression is variable, suggesting the existence of genetic modifiers of EGFR dependency in EGFR-mutant NSCLCs. Here, we applied a genome-wide CRISPR-Cas9 screening to identify genetic determinants of EGFR TKI sensitivity and uncovered both known and putative candidates. Specifically, we show that knockout of RIC8A, a guanine nucleotide exchange factor (GEF) essential for G-alpha protein activation, enhanced EGFR TKI-induced cell death and prevented acquired resistance. Mechanistically, we demonstrate that RIC8A is a potent positive regulator of the pro-survival YAP signaling pathway, activation of which rescued the EGFR TKI sensitizing phenotype resulting from RIC8A knockout. We also show that knockout of ARIH2, or other components in the Cullin-5 E3 ubiquitin ligase complex, conferred resistance to EGFR inhibition, in part by promoting nascent protein synthesis through METAP2. Together, these data uncover a spectrum of previously unidentified regulators of EGFR TKI sensitivity in EGFR-mutant NSCLC cells, providing insights into the heterogeneity of EGFR TKI treatment responses in EGFR-mutant NSCLCs.
HostingRepository	PRIDE
AnnounceDate	2019-11-14
AnnouncementXML	Submission_2019-11-13_23:32:52.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Debora Bonenfant
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetic acid derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-06-10 03:19:33	ID requested
⏵ 1	2019-11-13 23:43:51	announced
2	2019-11-27 06:53:46	announced	2019-11-27: Updated project metadata.
3	2020-01-14 06:25:07	announced	2019-11-27: Updated project metadata. 2020-01-14: Updated publication reference for PubMed record(s): 31741433.

Dataset with its publication pending

submitter keyword: human, cancer, EGFR

Debora Bonenfant
contact affiliation	Debora Bonenfant, Novartis Institutes for Biomedical research, Basel, Switzerland
contact email	debora.bonenfant@novartis.com
lab head
Debora Bonenfant
contact affiliation	Novartis Institutes for BioMedical Research
contact email	debora.bonenfant@novartis.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/2019/11/PXD014198

PRIDE project URI

• PRIDE
  1. PXD014198
     1. Label: PRIDE project
     2. Name: Genome-wide CRISPR screening reveals genetic modifiers of mutant EGFR dependence in NSCLC