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<p>Acute myeloid leukemia (AML) remains challenging to treat due to extensive genetic heterogeneity, high relapse rates, and treatment-related toxicity. Although drug combinations offer therapeutic promise, their selection is often empirical. Here, we introduce Combinatorial Proteome Integral Solubility/Stability Alteration analysis (CoPISA), a high-throughput proteomics workflow that captures protein solubility/stability alterations uniquely induced by drug combinations. We applied CoPISA to two rationally designed AML drug pairs, LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU), previously identified as the most effective and least toxic combinations among many candidates and validated in AML cell lines, patient-derived samples and zebrafish xenograft models. We uncovered an emergent mechanism termed “conjunctional targeting”, in which combinatorial drug action induces combination-exclusive protein targets consistent with an AND-gate logic model. LS-specific converged on SUMOylation, chromatin condensation, and VEGF-linked adhesion, while RU-specific targets disrupted DNA-damage checkpoints, mitochondrial bioenergetics, and RNA-splicing. Post-translational modification analysis revealed combination-induced acetylation, methylation, and phosphorylation of key AML proteins, including NPM1. Network analysis demonstrated that a substantial fraction of AML-associated proteins targeted by CoPISA are unique to combinations, including DNMT3A, NPM1, and TP53. By uncovering a mechanistic layer beyond classical synergy, CoPISA provides a robust framework for the precision-guided design of combinatorial therapies in heterogeneous cancers.</p>

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Solubility based mechanistic profiling of combinatorial drug therapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月25日

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  • Elham Gholizadeh,
  • Ehsan Zangene,
  • Uladzislau Vadadokhau,
  • Danilo Ritz,
  • Juho J. Miettinen,
  • Rabah Soliymani,
  • Marc Baumann,
  • Mathias Wilhelm,
  • Esko Kankuri,
  • Paul A. Haynes,
  • Caroline A. Heckman,
  • Amir A. Saei,
  • Mohieddin Jafari

摘要

Acute myeloid leukemia (AML) remains challenging to treat due to extensive genetic heterogeneity, high relapse rates, and treatment-related toxicity. Although drug combinations offer therapeutic promise, their selection is often empirical. Here, we introduce Combinatorial Proteome Integral Solubility/Stability Alteration analysis (CoPISA), a high-throughput proteomics workflow that captures protein solubility/stability alterations uniquely induced by drug combinations. We applied CoPISA to two rationally designed AML drug pairs, LY3009120-sapanisertib (LS) and ruxolitinib-ulixertinib (RU), previously identified as the most effective and least toxic combinations among many candidates and validated in AML cell lines, patient-derived samples and zebrafish xenograft models. We uncovered an emergent mechanism termed “conjunctional targeting”, in which combinatorial drug action induces combination-exclusive protein targets consistent with an AND-gate logic model. LS-specific converged on SUMOylation, chromatin condensation, and VEGF-linked adhesion, while RU-specific targets disrupted DNA-damage checkpoints, mitochondrial bioenergetics, and RNA-splicing. Post-translational modification analysis revealed combination-induced acetylation, methylation, and phosphorylation of key AML proteins, including NPM1. Network analysis demonstrated that a substantial fraction of AML-associated proteins targeted by CoPISA are unique to combinations, including DNMT3A, NPM1, and TP53. By uncovering a mechanistic layer beyond classical synergy, CoPISA provides a robust framework for the precision-guided design of combinatorial therapies in heterogeneous cancers.