Uncovering expression signatures of synergistic drug responses via ensembles of explainable machine-learning models

Machine learning may aid the choice of optimal combinations of anticancer drugs by explaining the molecular basis of their synergy. By combining accurate models with interpretable insights, explainable machine learning promises to accelerate data-driven cancer pharmacology. However, owing to the highly correlated and high-dimensional nature of transcriptomic data, naively applying current explainable machine-learning strategies to large transcriptomic datasets leads to suboptimal outcomes. Here by using feature attribution methods, we show that the quality of the explanations can be increased by leveraging ensembles of explainable machine-learning models. We applied the approach to a dataset of 133 combinations of 46 anticancer drugs tested in ex vivo tumour samples from 285 patients with acute myeloid leukaemia and uncovered a haematopoietic-differentiation signature underlying drug combinations with therapeutic synergy. Ensembles of machine-learning models trained to predict drug combination synergies on the basis of gene-expression data may improve the feature attribution quality of complex machine-learning models.