PXD063764

PXD063764 is an original dataset announced via ProteomeXchange.

Title	Functional and omics-based rationale for the induction of BRCAness by androgen receptor pathway inhibitors to sensitize prostate cancer to PARP inhibition, regardless of HRR status
Description	Two PARP inhibitors (PARPi) olaparib and talazoparib have been approved in combination with novel-hormonal-therapies (NHTs) for the treatment of metastatic castration resistant prostate cancer (mCRPC) – in Europe independent of the HRR status. However, the underlying mechanism of action in HRR negative patients is still not fully understood. In the current study, we revealed that combining PARPi (olaparib or talazoparib) with NHTs (abiraterone, enzalutamide, or apalutamide) significantly reduced cell survival in HS LNCaP and CR DU145 and 22RV1 PCa cell lines. While PDOs did not respond to olaparib alone, talazoparib mono-treatment reduced survival >2-fold in one LN-metastatic PDO and marginally (1.1-fold) in the other two. NHTs using abiraterone, enzalutamide or apalutamide all significantly reduced survival in the two LN-metastatic PDOs but were ineffective in the bone-metastatic PDOs. Importantly, the combination of any of the PARPi with any of the NHTs demonstrated significantly greater cytotoxic effects across all PDOs. None of these PDOs displayed a profile typically linked to BRCAness, as identified by the HRDetect score. Sequential (NHT followed by PARPi) and simultaneous treatment strategies yielded comparable results. Transcriptomic and immunoblotting analyses revealed that NHTs downregulate the homologous recombination repair gene RAD51, inducing a "BRCAness-like" phenotype characterized by reduced RAD51 foci formation at DNA double-strand break (DSB) sites, and sensitizing tumor cells to PARPi. Consistently, among the LN-metastatic TSCs, 67% exhibited a substantial reduction in DSB repair capacity when treated with the combined regime compared to monotherapies. Further, proteomic analyses indicate that olaparib may suppress metastasis by inhibiting key pro-metastatic pathways, including epithelial-mesenchymal transition and angiogenesis. Collectively, we provide a mechanistic rationale for integrating NHTs with PARPi, regardless of treatment sequence, in treating mPCa patients. NHT induces a BRCAness-like phenotype, rendering cells sensitive to PARPi. Additionally, we establish the potential of PARPi to suppress metastasis in mPCa during the treatment course.
HostingRepository	PRIDE
AnnounceDate	2026-07-10
AnnouncementXML	Submission_2026-07-10_13:29:49.896.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ayham Moustafa
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-08 06:24:34	ID requested
⏵ 1	2026-07-10 13:29:50	announced

10.1038/s41416-026-03518-7;

Elsesy ME, Moustafa A, Oh-Hohenhorst SJ, M, ü, ller C, Alawi M, Mair T, Siebels B, Hu Z, Hahn J, Burdak-Rothkamm S, Tilki D, Schl, ü, ter H, Petersen C, Maurer T, von Amsberg G, Bokemeyer C, Rothkamm K, Mansour WY, Functional and omics-based rationale for the induction of BRCAness by androgen receptor pathway inhibitors to sensitize prostate cancer to PARP inhibition, regardless of HRR status. Br J Cancer, ():(2026) [pubmed]

submitter keyword: Hormon therapy, Organoids, Proteomics,Prostate cancer

Prof. Dr. Wael Mansour
contact affiliation	Targeting DNA repair in systemic and radiation cancer therapy II.Medical Oncology Dept, Radiotherapy and Radiooncology Dept Research team leader: DSB repair in tumors Mildred Scheel Nachwuchszentrum HaTriCS4
contact email	w.mansour@uke.de
lab head
Ayham Moustafa
contact affiliation	Department of Radiotherapy and Radiooncology & Section for Mass spectrometry proteomics_ University Medical Center Hamburg Eppendorf, Hamburg, Germany
contact email	a.moustafa@uke.de
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/2026/07/PXD063764

PRIDE project URI

• PRIDE
  1. PXD063764
     1. Label: PRIDE project
     2. Name: Functional and omics-based rationale for the induction of BRCAness by androgen receptor pathway inhibitors to sensitize prostate cancer to PARP inhibition, regardless of HRR status