One-Hot News: Drug Synergy Models Shortcut Molecular Features

Combinatorial drug therapy holds great promise for tackling complex diseases, but the vast number of possible drug combinations makes exhaustive experimental testing infeasible. Computational models have been developed to guide experimental screens by assigning synergy scores to drug pair–cell line combinations, where they take input structural and chemical information on drugs and molecular features of cell lines. The premise of these models is that they leverage this biological and chemical information to predict synergy measurements. In this study, we demonstrate that replacing drug and cell line representations with simple one-hot encodings results in comparable or even slightly improved performance across diverse published drug combination models. This unexpected finding suggests that current models use these representations primarily as identifiers and exploit covariation in the synergy labels. Our synthetic data experiments show that models can learn from the true features; however, when drugs and cell lines recur across drug–drug–cell triplets, this repeating structure impairs feature-based learning. While the current synergy prediction models can still aid in prioritizing drug pairs within a panel of tested drugs and cell lines, our results highlight the need for better strategies to learn from intended features and generalize to unseen drugs and cell lines.