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.

B 细胞淋巴瘤 2 (BCL2) 同源 3 (BH3) 模拟物是蛋白质-蛋白质相互作用 (PPI) 的抑制剂，可饱和 BCL2 家族中的抗凋亡蛋白，从而诱导癌细胞凋亡。尽管 BH3 模拟物 ABT-199 在治疗血液恶性肿瘤方面取得了成功，但只有一小部分患者对该药物有反应，大多数患者最终对其产生耐药性。在这里，我们表明，可以通过单分子下拉和免疫共沉淀分析 BCL2 家族 PPI 网络的重新连接状态来预测 ABT-199 的功效，从而量化总共 20 多种 PPI每个样品 1.2 × 10 ^{6 个}细胞。通过将获得的多维数据与体外确定的 BH3 模拟功效进行比较，我们构建了一个预测 ABT-199 功效的模型，该模型将 BCL2 蛋白家族的两个复合物指定为药物有效性和耐药性的主要介质，并将其应用于前瞻性地协助急性髓系白血病患者的治疗决策。临床样本中 PPI 复合物的表征为个体化蛋白质复合物靶向治疗开辟了机会。