PXD029972

PXD029972 is an original dataset announced via ProteomeXchange.

Title	Induced Degradation of Lineage-specific Oncoproteins Underlies the Selective PARP1 Inhibitor Toxicity in Small Cell Lung Cancer
Description	A subset of small cell lung cancer (SCLC) shows a clinical response to PARP inhibitors (PARPi) despite being proficient in homologous repair pathways. However, the underlying mechanism(s) of PARPi sensitivity is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in a large panel of molecularly annotated patient-derived SCLC lines. We found that the toxicity of PARPi in SCLC is explained by the PARPi-induced degradation of key lineage-specific oncoproteins including ASCL1, NEUROD1, POU2F3, KDM4A, and KDM5B. Biochemical experiments showed that PARPi-induced activation of E3 ligases (e.g., HUWE1 and RNF8) mediated the ubiquitin-proteasome system (UPS)-dependent degradation of these oncoproteins. Interestingly, although PARPi resulted in a general DNA damage response, this signal is sensed by different SCLC cell lines to generate a cell-specific response. The dissection of the cell-specific oncoprotein degradation response led to the identification of potentially predictive biomarkers for PARPi in SCLC. The combination of PARPi and agents targeting these pathways led to dramatically improved cytotoxicity in SCLC. PARPi-induced degradation of lineage-specific oncoproteins therefore represents a novel mechanism to explain the efficacy of PARPi in tumors without homologous recombination deficiency.
HostingRepository	PRIDE
AnnounceDate	2024-01-26
AnnouncementXML	Submission_2024-01-26_06:24:08.157.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Xu-Dong Wang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-26 05:20:33	ID requested
⏵ 1	2024-01-26 06:24:09	announced

10.1126/sciadv.adh2579;

Kim C, Wang XD, Liu Z, Hao J, Wang S, Li P, Zi Z, Ding Q, Jang S, Kim J, Luo Y, Huffman KE, Pal Choudhuri S, Del Rio S, Cai L, Liang H, Drapkin BJ, Minna JD, Yu Y, Induced degradation of lineage-specific oncoproteins drives the therapeutic vulnerability of small cell lung cancer to PARP inhibitors. Sci Adv, 10(3):eadh2579(2024) [pubmed]

submitter keyword: Quantitative proteomics, ASCL1, lineage-specific oncoproteins, synergistic effect, PiPS, PARP1 inhibitor, predictive biomarkers, a histone demethylase, BRCA1/2, small cell lung cancer, homologous recombination

Yonghao Yu
contact affiliation	Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA
contact email	yonghaoyu@utsouthwestern.edu
lab head
Xu-Dong Wang
contact affiliation	UT Southwestern Medical Center
contact email	Xu-Dong.Wang@utsouthwestern.edu
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/2024/01/PXD029972

PRIDE project URI

• PRIDE
  1. PXD029972
     1. Label: PRIDE project
     2. Name: Induced Degradation of Lineage-specific Oncoproteins Underlies the Selective PARP1 Inhibitor Toxicity in Small Cell Lung Cancer