Profiling protein-protein interactions to predict the efficacy of B-cell-lymphoma-2-homology-3 mimetics for acute myeloid leukaemia

  • Nat Biomed Eng. 2024 Jul 18. doi: 10.1038/s41551-024-01241-3.
Changju Chun  #  1 ,  Ja Min Byun  #  2 ,  Minkwon Cha  #  1  3 ,  Hongwon Lee  4 ,  Byungsan Choi  4 ,  Hyunwoo Kim  4 ,  Saem Hong  4 ,  Yunseo Lee  4 ,  Hayoung Park  4  1 ,  Youngil Koh  5 ,  Tae-Young Yoon  6  7
Affiliations
  • 1. School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul, South Korea.
  • 2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea.
  • 3. Department of Physics, Pohang University of Science and Technology (POSTECH), Pohang, South Korea.
  • 4. Department of Biomarker Discovery, PROTEINA Co., Ltd, Seoul, South Korea.
  • 5. Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea. [email protected].
  • 6. School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul, South Korea. [email protected].
  • 7. Department of Biomarker Discovery, PROTEINA Co., Ltd, Seoul, South Korea. [email protected].
  • # Contributed equally.
PMID: 39025942 DOI: 10.1038/s41551-024-01241-3
Abstract

B-cell-lymphoma-2 (BCL2) homology-3 (BH3) mimetics are inhibitors of protein-protein interactions (PPIs) that saturate anti-apoptotic proteins in the BCL2 family to induce Apoptosis in Cancer cells. Despite the success of the BH3-mimetic ABT-199 for the treatment of haematological malignancies, only a fraction of patients respond to the drug and most patients eventually develop resistance to it. Here we show that the efficacy of ABT-199 can be predicted by profiling the rewired status of the PPI network of the BCL2 family via single-molecule pull-down and co-immunoprecipitation to quantify more than 20 types of PPI from a total of only 1.2 × 106 cells per sample. By comparing the obtained multidimensional data with BH3-mimetic efficacies determined ex vivo, we constructed a model for predicting the efficacy of ABT-199 that designates two complexes of the BCL2 protein family as the primary mediators of drug effectiveness and resistance, and applied it to prospectively assist therapeutic decision-making for patients with acute myeloid leukaemia. The characterization of PPI complexes in clinical specimens opens up opportunities for individualized protein-complex-targeting therapies.

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