PXD054120

PXD054120 is an original dataset announced via ProteomeXchange.

Title	Investigating Synthetic Lethality and PARP Inhibitor Resistance in Pancreatic Cancer Through Enantiomer Differential Activity
Description	The RAD51-BRCA2 interaction is central to DNA repair through homologous recombination. Emerging evidence indicates RAD51 overexpression and its correlation with chemoresistance in various cancers, suggesting RAD51-BRCA2 inhibition as a compelling avenue for intervention. We previously showed that combining olaparib (a PARP inhibitor (PARPi)) with RS-35d (a BRCA2-RAD51 inhibitor) was efficient in killing pancreatic ductal adenocarcinoma (PDAC) cells. However, RS-35d impaired cell viability even when administered alone, suggesting potential off-target effects. Here, through multiple, integrated orthogonal biological approaches in different 2D and 3D PDAC cultures, we characterised RS-35d enantiomers, in terms of mode of action and single contributions. By differentially inhibiting both RAD51-BRCA2 interaction and sensor kinases ATM, ATR and DNA-PK, RS-35d enantiomers exhibit a "within-pathway synthetic lethality" profile. To the best of our knowledge, this is the first reported proof-of-concept single small molecule capable of demonstrating this built-in synergism. In addition, RS-35d effect on BRCA2-mutated, olaparib-resistant PDAC cells suggests that this compound may be effective as an anticancer agent possibly capable of overcoming PARPi resistance. Our results demonstrate the potential of synthetic lethality, with its diversified applications, to propose new and concrete opportunities to effectively kill cancer cells while limiting side effects and potentially overcoming emerging drug resistance.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-06_21:43:54.592.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kieran Wynne
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-22 10:46:47	ID requested
⏵ 1	2025-05-06 21:43:55	announced

10.1038/s41420-025-02382-3;

Masi M, Poppi L, Previtali V, Nelson SR, Wynne K, Varignani G, Falchi F, Veronesi M, Albanesi E, Tedesco D, De Franco F, Ciamarone A, Myers SH, Ortega JA, Bagnolini G, Ferrandi G, Farabegoli F, Tirelli N, Di Stefano G, Oliviero G, Walsh N, Roberti M, Girotto S, Cavalli A, Investigating synthetic lethality and PARP inhibitor resistance in pancreatic cancer through enantiomer differential activity. Cell Death Discov, 11(1):106(2025) [pubmed]

submitter keyword: Anticancer drugs

Homologous recombination

PARP inhibitors

Protein-protein small molecule inhibitors

PARPi resistance

within-pathway synthetic lethality (wpSL)

Prof Andrea Cavalli
contact affiliation	Senior Researcher - Principal Investigator, Computational and Chemical Biology, Istituto Italiano di Tecnologia Via Morego, 30 16163 Genova - Italy Tel: +39 010 28961 - C.F.: 97329350587 - P.Iva: 09198791007
contact email	andrea.cavalli@iit.it
lab head
Kieran Wynne
contact affiliation	University College Dublin
contact email	kieran.wynne1@ucd.ie
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/2025/05/PXD054120

PRIDE project URI

• PRIDE
  1. PXD054120
     1. Label: PRIDE project
     2. Name: Investigating Synthetic Lethality and PARP Inhibitor Resistance in Pancreatic Cancer Through Enantiomer Differential Activity