PXD048813

PXD048813 is an original dataset announced via ProteomeXchange.

Title	An in vivo screening platform using PDX models reveals KEAP1, USP22 and other drivers of chemoresistance in small cell lung cancer
Description	Small cell lung cancer (SCLC) is characterized by exquisite chemosensitivity followed by rapid emergence of chemoresistance. To identify genetic events that drive resistance to cisplatin-etoposide chemotherapy, we conducted cDNA overexpression and CRISPR knockout screens in an in vivo platform centered on chemosensitive patient derived xenograft (PDX) models of SCLC. cDNA overexpression screens revealed MYC, MYCN and MYCL as drivers of tumor cell growth through chemotherapy. CRISPR knockout screens identified the KEAP1/NRF2 pathway and members of the SAGA (Spt-Ada-Gcn5 acetyltransferase) complex, including the deubiquitylase USP22. We demonstrated that knockout of either KEAP1 or USP22 switches chemosensitive PDX models to become chemoresistant, with our data supporting distinct molecular consequences, including suppression of DNA damage signaling upon USP22 deletion. Data from the IMpower133 clinical trial revealed that a substantial proportion of SCLC patients exhibit KEAP1/NFE2L2 genetic alterations, with activation of an NRF2 transcriptional signature associated with reduced SCLC patient survival with chemotherapy.
HostingRepository	PRIDE
AnnounceDate	2026-04-20
AnnouncementXML	Submission_2026-04-20_10:55:18.502.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jacob Kennedy
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-23 15:12:19	ID requested
⏵ 1	2026-04-20 10:55:19	announced

Dataset with its publication pending

submitter keyword: CRISPR knockout, global phosphoproteome,Small cell lung cancer, IMAC, TMT, PDX

David MacPherson
contact affiliation	Professor, Human Biology, Fred Hutchinson Cancer Center, USA
contact email	dmacpher@fredhutch.org
lab head
Jacob Kennedy
contact affiliation	Fred Hutchinson Cancer Research Center
contact email	jkennedy@fhcrc.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD048813
     1. Label: PRIDE project
     2. Name: An in vivo screening platform using PDX models reveals KEAP1, USP22 and other drivers of chemoresistance in small cell lung cancer