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Profiling protein-protein interactions to predict the efficacy of B-cell-lymphoma-2-homology-3 mimetics for acute myeloid leukaemia.
Chun, Changju; Byun, Ja Min; Cha, Minkwon; Lee, Hongwon; Choi, Byungsan; Kim, Hyunwoo; Hong, Saem; Lee, Yunseo; Park, Hayoung; Koh, Youngil; Yoon, Tae-Young.
Afiliación
  • Chun C; School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul, South Korea.
  • Byun JM; Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea.
  • Cha M; School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul, South Korea.
  • Lee H; Department of Physics, Pohang University of Science and Technology (POSTECH), Pohang, South Korea.
  • Choi B; Department of Biomarker Discovery, PROTEINA Co., Ltd, Seoul, South Korea.
  • Kim H; Department of Biomarker Discovery, PROTEINA Co., Ltd, Seoul, South Korea.
  • Hong S; Department of Biomarker Discovery, PROTEINA Co., Ltd, Seoul, South Korea.
  • Lee Y; Department of Biomarker Discovery, PROTEINA Co., Ltd, Seoul, South Korea.
  • Park H; Department of Biomarker Discovery, PROTEINA Co., Ltd, Seoul, South Korea.
  • Koh Y; Department of Biomarker Discovery, PROTEINA Co., Ltd, Seoul, South Korea.
  • Yoon TY; School of Biological Sciences and Institute for Molecular Biology and Genetics, Seoul National University, Seoul, South Korea.
Nat Biomed Eng ; 2024 Jul 18.
Article en En | MEDLINE | ID: mdl-39025942
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nat Biomed Eng Año: 2024 Tipo del documento: Article País de afiliación: Corea del Sur Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Nat Biomed Eng Año: 2024 Tipo del documento: Article País de afiliación: Corea del Sur Pais de publicación: Reino Unido