Profiling Protein-protein Interactions to Predict the Efficacy of B-cell-lymphoma-2-homology-3 Mimetics for Acute Myeloid Leukaemia

Overview

Journal Nat Biomed Eng

Publisher Springer Nature

Specialty Biomedical Engineering

Date 2024 Jul 18

PMID 39025942

Authors

Changju Chun

Ja Min Byun

Minkwon Cha

Hongwon Lee

Byungsan Choi

Hyunwoo Kim

Saem Hong

Yunseo Lee

Hayoung Park

Youngil Koh

Tae-Young Yoon

Affiliations

Soon will be listed here.

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 × 10 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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