PXD066812

PXD066812 is an original dataset announced via ProteomeXchange.

Title	Shifting Beyond Classical Drug Synergy in Combinatorial Therapy through Solubility Alterations
Description	Acute myeloid leukemia (AML) poses a major clinical challenge due to its genetic diversity, relapse rates, and chemotherapy toxicity. While rational drug combinations improve efficacy, their mechanisms remain poorly understood. We introduce CoPISA (Proteome Integral Solubility/Stability Alteration Analysis for Combinations), a high-throughput proteomics workflow that identifies protein solubility/stability changes unique to drug combinations. Applied to two AML drug pairs—LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU)—CoPISA mapped protein targets in lysates and living cells. The analysis revealed a novel principle, “conjunctional targeting”, where drug pairs induce unique, cooperative effects not seen with individual drugs, akin to an AND-gate logic. LS-specific targets involved SUMOylation, chromatin condensation, and VEGF-linked adhesion; RU-specific targets disrupted DNA damage checkpoints, mitochondrial function, and RNA splicing, suggesting synthetic-lethal vulnerabilities. Post-translational modification profiling confirmed combination-induced changes (e.g., acetylation, dimethylation, phosphorylation) on key AML proteins like NPM1. Network analysis showed many targets were unique to combinations, including frequently mutated drivers DNMT3A, NPM1, and TP53. CoPISA reveals how drug pairs exert multi-axis pressure on AML cells, offering a mechanistic layer beyond classical synergy and guiding precision therapy design for AML and other complex cancers.
HostingRepository	PRIDE
AnnounceDate	2026-02-12
AnnouncementXML	Submission_2026-02-12_09:23:47.500.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Uladzislau Vadadokhau
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	asymmetric dimethyl-L-arginine; phosphorylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-31 10:14:27	ID requested
⏵ 1	2026-02-12 09:23:48	announced

10.1101/2024.11.08.618644;

submitter keyword: combination therapy,Acute myeloid leukaemia, Proteome Integral Solubility Alteration assay for combinations, CoPISA

Mohieddin Jafari
contact affiliation	Systems Pharmacology lab, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Finland
contact email	mohieddin.jafari@helsinki.fi
lab head
Uladzislau Vadadokhau
contact affiliation	University of Helsinki
contact email	uladzislau.vadadokhau@helsinki.fi
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD066812
     1. Label: PRIDE project
     2. Name: Shifting Beyond Classical Drug Synergy in Combinatorial Therapy through Solubility Alterations