Solubility based mechanistic profiling of combinatorial drug therapy

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Cell Suspension Culture

DISEASE(S): Acute Myeloid Leukemia

SUBMITTER: Uladzislau Vadadokhau  

LAB HEAD: Mohieddin Jafari

PROVIDER: PXD066812 | Pride | 2026-02-12

REPOSITORIES: Pride